Study, clinical

Conducting a clinical trial

• Clinical trials in the pharmaceutical industry are carried out by the pharmaceutical companies themselves or by service providers with the necessary expertise (Contract Research Organisations). The data collected are entered into suitable clinical database management systems (CDBMS). Once all patients have completed a study (there are also drop-outs who discontinue participation in studies due to various events), the CDBMS is locked for entries (database lock). The previously planned statistical analyses are then carried out and corresponding reports are generated. Depending on the purpose of the study (marketing study, phase I or III study), the report serves as the basis for publication or is part of a marketing authorization application.

Planning and execution

• Determination of a study program, target direction and rough planning of the sequence of several studies in succession; preparation of a study protocol, which includes:
  • the objectives and hypothesis to be tested,
  • the study design,
  • the treatment (drug, dosage, etc.),
  • the statistical evaluation methods,
  • the inclusion and exclusion criteria for patients,
  • the measurements to be collected (standard laboratory values such as blood values, urine tests, liver values as well as special measurements of biomarkers, etc.)
  • The visit planning (at which measured values are collected)
  • discontinuation criteria for a patient.
• The study protocol must be approved by regulatory authorities.

Sponsor:

• Natural or legal person who assumes responsibility for initiating, organizing and financing a clinical trial in humans (Section 4 (24) AMG).

Sponsor:

• Mostly the pharmaceutical industry (see also pharmaceutical research), university institutes and affiliated research institutions, which are not infrequently sponsored by the pharmaceutical industry via third-party funds, as well as governmental, semi-governmental and other non-profit health care institutions.

Investigator:

• Usually a physician responsible for conducting a human clinical trial at a trial site. If a trial is conducted in a trial site by more than one investigator, the responsible head of the group is the principal investigator. If a trial is conducted at more than one trial site, one investigator is designated by the sponsor as the principal investigator (Section 4(25) AMG).

Head of the clinical trial (LKP):

• The GCP guideline does not provide for the person of the head of the clinical trial. However, the implementation by the 12th AMG amendment took place without renouncing the person of the head of the clinical trial. In the case of multicentre studies, one of the participating investigators should take the position of the head of the clinical trial. In the case of monocentric trials, this is replaced by the principal investigator or the sole investigator. Regarding the qualification of the principal investigator, according to § 40 para. 1 sentence 3 no. 5 AMG, a minimum of two years of experience in clinical trials of medicinal products is required.

Investigational medicinal product:

• Dosage forms of active substances or placebos that are tested in a clinical trial in humans or used as comparator preparations or used to induce specific reactions in humans. This includes medicinal products that are not authorised and authorised medicinal products if they are used in the context of a clinical trial in humans in a dosage form other than the authorised dosage form or for an unauthorised indication or to obtain additional information on the authorised medicinal product (Section 3 (3) GCP-V).

Ethics Committee:

• An independent body composed of health care and non-medical professionals whose task is to ensure the protection of the rights, safety and well-being of data subjects within the meaning of paragraph 2a and to provide public confidence in this respect by commenting, inter alia, on the protocol, the suitability of the investigators and the adequacy of the facilities, as well as on the methods used to inform data subjects and to obtain their informed consent and on the information material used in this process. (Section 3 (2c) GCP-V).

Good Clinical Practice (GCP)

• According to the EU Directive 2001/20 Art. 1 Sentence 2, "good clinical practice" is defined as follows: it comprises a catalogue of internationally recognised ethical and scientific quality requirements that must be observed in the planning, conduct and recording of clinical trials involving human subjects, as well as in the reporting of these trials. Compliance ensures that the rights, safety and well-being of clinical trial participants are protected and that the results of clinical trials are credible.

Phases in the development of a medicinal product:

• The development of a drug is divided into different clinical phases (Phase 0 to Phase IV). This division is based on the "Code of Federal Regulations" of the US Food and Drug Administration (FDA). Approval for a study in a particular phase is granted by the relevant regulatory authority if the preceding study phase has been successfully completed.

Preclinical phase (Phase 0 study: pharmacokinetic study, pharmacodynamics, tests with subtherapeutic doses, e.g. microdosing)

• A drug has to pass a preclinical phase before going through phase I. Only about 8 % of the preclinically tested active substances have a chance of obtaining approval or marketability due to various deficiencies (e.g. lack of efficacy or unfavourable pharmacokinetics of the new active substance in humans). .

Phase I study (pharmacokinetics, pharmacodynamics, tolerability and safety of the drug)

• In a Phase I study, the tolerability of the drug is first tested on a small group of study participants. The study also investigates the best dosage for administering the new drug, how the drug is absorbed and excreted in the body, and how it is distributed.

Phase II study (Phase II Verification of the therapy concept (Proof of Concept, Phase IIa), finding the appropriate therapy dose (Dose Finding, Phase IIb), positive effects of the therapy should be observed)

• The Phase II study builds on the information and initial experience gained in the Phase I study. Here, the optimal dosage range is determined (dose finding). Phase II dose-finding studies often test 4 or more doses simultaneously (e.g., randomized, double-blind, and placebo-controlled).

Phase III study (significant proof of efficacy (pivotal study) and marketing approval of the therapy; after marketing approval, ongoing studies then become IIIb studies)

• The aim of a Phase III trial is to prove the efficacy of a new drug. A phase III trial involves a large number of patients (>100 to 1000) who must meet certain inclusion and exclusion criteria. The result of the Phase III study is decisive for the final decision of the BfArM (German Federal Institute for Drugs and Medical Devices) as to whether approval is granted.

Phase IV study (Success with already approved drugs in the approved indication. Regulatory authorities often require such studies, e.g. to identify very rare side effects that can only be detected in large patient collectives. Phase IV studies are also frequently used for marketing purposes).

• After approval, a drug can continue to be investigated in a Phase IV study. In this case, a much larger group of patients can be included in the study. These include patients who were previously excluded, e.g. elderly patients or patients with secondary or multiple diseases.

Special features There are situations in which controlled and randomised studies are not or only with difficulty feasible. The reasons for this are e.g.:

• Rarity of the disease (orphan disease)
• exclusion of a control group for ethical reasons (it must be assumed that the active substance to be tested has a serious therapeutic advantage)
• invasive therapies (e.g. a sham operation would have to be performed)

For these cases, the legislator provides alternative study types:

• Case-control study
• Cohort study
• pre-post-study.

The statements of such studies allow only limited conclusions about the investigated form of therapy. Within the framework of evidence-based medicine, efforts are made to establish as good a scientific basis as possible for each therapeutic procedure. Therapy Optimization Trials (TOP)

• In these trials, different treatment methods with proven efficacy are usually applied in a different time sequence or with different dosage regimens, or are combined in a new way. The difference to the commonly used therapy is not very big, the risk for the involved patient is low.