A clinical study is a form of survey in evidence-based medicine and clinical research . It is carried out with patients or healthy volunteers and is a prerequisite for drug approval by the authorities .
The aim is to check drugs , certain forms of treatment, medical interventions or medical devices for their effectiveness and safety. Clinical studies are carried out to answer scientific questions and improve medical treatment.
The first use of a promising medical treatment on humans should therefore be a clinical study with the aim of testing the effectiveness and tolerability of new therapies. However, such a study can only take place if sufficient data are available to ensure that it can be carried out safely and there is a positive vote from the responsible ethics committee . In order to minimize external disturbances, such studies are carried out in a controlled environment.
Controlled clinical trials test medical intervention on patients, comparing two or more groups of patients. The so-called verum group receives the treatment that is to be tested, and the control group receives, for example, an alternative treatment or placebo . Both groups are followed up and compared to determine whether the treatment effect of the verum group was better than that of the control group (or not).
|Classification of clinical studies|
A distinction is made between intervention studies and observational studies (see figure). Randomization is of great importance in the study design to be chosen . This is almost always done in controlled studies, usually in combination with blinding . In a double-blind study, neither the investigator nor the patient must know which therapy group the patient is assigned to. The blinding can prevent conscious and unconscious influences on the treatment result and thus increase the credibility of the study and its results. Selection effects can only be avoided if the randomization codes are strictly confidential. Controlled studies are particularly necessary to prove effectiveness; However, there are exceptions, for example if a control group is not ethically justifiable (e.g. no sufficiently effective control drug is available). Controlled studies can occasionally not be blinded, for example if one of the groups has to undergo an invasive procedure (e.g. surgery) and a “sham procedure” in the comparison group would be unethical. Other important aspects of study planning and implementation are:
- Study registration (see below)
- Test plan (English: Protocol )
- Selection of subjects / patients (inclusion and exclusion criteria)
- Definition of the parameters to be measured
- Type of dosage
- Type of control group
- Method for data evaluation
The clinical test of drugs is an examination carried out on humans, which is intended to research or prove clinical or pharmacological effects of drugs or to determine side effects (Section 4, Paragraph 23 of the German Medicines Act, AMG ). As part of the development of a new therapeutic approach, the clinical studies represent the last step in a long development towards the finished drug. They are an important part of university pharmaceutical research , which is essentially about the tolerability and / or effectiveness of drugs . Depending on the question, many types of studies can be used, for example for the evaluation of new surgical or radiological therapy approaches or medical devices whose design is laid down in the Medical Devices Act. Depending on the stage of development of the intervention, smaller pilot studies or large mega-studies can be carried out.
Adaptive study design in the development of new drugs
Since the number and scope of clinical studies and the associated costs and burdens for patients have increased significantly in recent years, the pharmaceutical industry is increasingly relying on adaptive study design.
Its basic principle is that a conventional clinical study makes certain assumptions for a model that do not quite accurately reflect reality. The incorrect assumptions lead z. B. to unnecessarily large or too low patient numbers.
Example 1: The variability of a measurement parameter of the study. The variability of a parameter to be determined is an essential influencing factor for the number of patients required to test a hypothesis, e.g. B. the effectiveness of a therapy.
The procedure now is to divide a study into two parts, the learning phase and the confirmation phase. In the learning phase, the assumptions of the original study plan are checked. If one recognizes z. B. in the learning phase that the variability of a parameter is lower than assumed, the originally planned number of patients can be reduced and the hypothesis to be tested can nevertheless be tested or refuted with sufficient certainty.
Example 2: In phase II studies to determine the dose, four or more doses are often checked simultaneously in parallel (e.g. randomized, double-blind and placebo-controlled). But it can happen that one realizes in the learning phase that z. B. the lowest dosage is ineffective and only higher dosages show the desired effect. After the learning phase, the study arm with the lowest dose is therefore terminated; the remaining three doses are investigated further in the confirmation phase.
Studies in which all but one of the study arms are discontinued due to relative failure may be continued in order to promote the use of the therapy protocol used in this arm, which has been found to be superior to the other arms.
Planning and execution
- Definition of a study program, target direction and rough planning of the sequence of several studies one after the other
- Test plan (planning a single study within a program). A test plan is created, which u. a .:
- the goals 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 measured values to be collected (standard laboratory values such as blood values, urine tests, liver values and special measured values of biomarkers, etc.),
- the visit planning (on which measured values are collected) and
- Contains termination criteria for a patient. The study protocol must be approved by the authorities.
- Patient recruitment. In a screening phase, demographic values (e.g. gender, age, weight, etc.) as well as laboratory values, etc., of candidates for the study are collected. If a candidate meets the inclusion criteria, they will be included in the study after approval.
- Carrying out the study. The clinical studies in the pharmaceutical industry are carried out by the pharmaceutical companies themselves or by specialized service providers ( contract research organizations ). The collected data are entered into a clinical database management system (CDBMS) and into a LIMS system. If all patients have completed the study (there are also drop-outs which terminate participation in studies due to various events), the CDBMS is blocked for entries (database lock).
- Statistical analysis ( biostatistics ). After the database lock, the planned statistical analyzes are 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 an application for approval.
History and Other Types of Study
In Germany was thalidomide - (thalidomide) scandal in which the unwanted and serious side effects remained unnoticed for long one of the main reasons for the setting stricter rules for the introduction of new drugs.
In some cases, however, controlled and randomized studies are impossible or difficult to carry out. Reasons for this can be:
- the rarity of the disease
- Exclusion of a control group for ethical reasons if it can be assumed that the active substance to be tested has a serious therapeutic advantage
- invasive therapies (for example, if a sham operation would have to be performed)
Therefore, there are also less rigorous study types, such as the case-control study , the cohort study or the pre-post study . These only permit statements with a certain degree of uncertainty about the type of therapy examined. In the context of evidence-based medicine , attempts are now being made to create the best possible scientific basis for every therapeutic approach. At the top is the meta-analysis of several randomized studies, at the bottom the expert opinion, with the studies cited in between.
In March 2006, the monoclonal antibody TGN1412 , which was to be used therapeutically for autoimmune diseases , caused a catastrophic inflammatory reaction in the six test subjects in a clinical phase I study in London and, as a result, multiple organ failure, which those affected barely survived .
Phases of a drug trial
The development of a drug is divided into so-called clinical phases. This division goes back to the Code of Federal Regulations of the US agency FDA. Approval for a study in the next higher phase is usually only granted by the relevant supervisory authority if the previous study phase has been successfully completed.
|0||approx. 10-15||Weeks||Pharmacokinetics , pharmacodynamics , tests with sub-therapeutic doses, e.g. B. Microdosing|
|I.||approx. 20-80||Weeks to months||First-time use on healthy volunteers, pharmacokinetics, pharmacodynamics, tolerability and safety of the drug|
|II||approx. 50-200||Months||Review of the therapy concept ( proof of concept , phase IIa), determination of the appropriate therapy dose ( dose finding , phase IIb), positive effects of the therapy should be observed|
|III||approx. 200-10,000||Months to years||Significant proof of effectiveness ( pivot study ) and marketing authorization of the therapy; After market approval, ongoing studies then become IIIb studies|
|IV||from approx. 1000 to millions||Years||Successes with already approved drugs in the approved indication. Licensing authorities often require such studies, e.g. B. to determine very rare side effects that are only recognizable in large patient groups. Phase IV studies are often used for marketing purposes|
A typical active ingredient has undergone around a decade of preclinical studies before going into the 1st clinical study phase (phase I) . According to an FDA publication (2004), such an active ingredient has an 8% chance of ultimately gaining approval or market readiness . In most cases, this is due to a lack of effectiveness or unfavorable pharmacokinetics of the new active ingredient in humans. Around 10% of all active ingredients in clinical studies fail because of unexpected side effects in humans despite the previous animal experiments , 30% of the toxic effects that occur in humans alone are not predicted by animal experiments. Because of this uncertainty, caution must be exercised when first using it on humans.
Clinical testing of medical devices
As with pharmaceuticals, clinical studies in the form of clinical trials are also carried out for medical devices . Clinical tests must be carried out for all medical devices, unless the use of existing clinical data is sufficiently justified. A clinical trial is generally required if any of the following applies:
- It is a completely new type of medical device (i.e. there is no literature on a comparable product or there is no comparable product).
- An existing medical device was modified in such a way that a significant impact on clinical safety and performance can be expected.
- It is a medical device with a new indication.
- New, previously unknown material is used or a known material is used in a new anatomical region of the body or the medical device is used over the long term.
The objective of the clinical trial and the study plan based on it are based on a clinical evaluation . The implementation of clinical tests on medical devices is based on the same requirements as for the pharmaceutical sector. It requires a dedicated test plan according to DIN EN ISO 14155 by a qualified head of the clinical test ( investigator ), proof of the safety of the product in question, approval from the competent higher federal authority BfArM ( § 22a MPG), the approving evaluation of the according to § 22 para. 1 MPG responsible ethics committee ( § 20 para. 1 MPG), the information and consent of the patient and the conclusion of a test subject insurance. Further details are regulated in Germany in the Ordinance on Clinical Trials of Medical Devices (MPKPV) and in the Medical Device Safety Plan Ordinance (MPSV).
The quality requirements for clinical testing of medical devices (standard EN ISO 14155 - clinical testing of medical devices on humans) and drug studies ( guideline for good clinical practice , ICH E6 (R1)) are comparable. In contrast to pharmacological studies, it is often not possible to use a placebo for medical devices (e.g. implants or active medical devices). In these cases, however, it is sometimes possible to carry out a comparative study against the use of a medical device that is established on the market.
The results of the clinical trial are assessed together with existing clinical data (e.g. from specialist scientific literature) in the clinical evaluation. As part of the conformity assessment procedure, they serve to demonstrate the conformity of the product with the regulatory requirements.
Sponsors and financiers
The most important financiers of clinical studies are the pharmaceutical industry (see also pharmaceutical research ) and state sponsors (e.g. the BMBF or the DFG ). The sponsor of a clinical trial, on the other hand, is a natural or legal person who takes responsibility for initiating, organizing and financing a clinical trial in humans. With the implementation of the European GCP guideline , a sponsor has become necessary for every clinical trial with drugs or medical devices.
The sponsor is usually not the financier of the study. For example, if a university institute would like to conduct a study within the framework of a BMBF funding guideline, the sponsor is not the BMBF, but usually the university. To ensure a correct clinical trial, the sponsor can delegate sponsorship duties to third parties.
All renowned peer-reviewed journals explicitly require the financier to be named in the publication for reasons of transparency, in order to enable the reader to see through any interest-based results (e.g. if a drug from the financier turns out to be superior to a competing product in the study ). In the USA, this procedure is mandatory, while in Germany the financier has only been named as a voluntary commitment so far (2007).
Several studies showed that financing the pharmaceutical industry causes statistically significant discrepancies in the published study results in favor of the interests of the financier. This problem is examined in detail in the two-part article Financing of Drug Studies by Pharmaceutical Companies and the Consequences of the German Medical Journal .
“When evaluating a drug, information from published studies that were funded by pharmaceutical companies often leads to a distorted picture. This is not explained by the methodological quality of the drug studies. "
“Financing from a pharmaceutical company has an impact in various areas in the course of a drug trial and often leads to a positive result for the pharmaceutical sponsor. Public access to study protocols and results must be guaranteed. In addition, more drug studies should be carried out that are independently financed by pharmaceutical companies. "
European and national legal regulations
The following documents must be observed when planning and conducting clinical studies:
- Directive 2001/20 / EC on the application of good clinical practice of the European Parliament and of the Council of April 4, 2001 on the harmonization of the legal and administrative provisions of the member states on the application of good clinical practice when conducting clinical trials with medicinal products for human use
- Directive 2005/28 / EC on principles and guidelines of good clinical practice of the Commission of April 8, 2005 laying down principles and detailed guidelines of good clinical practice for investigational medicinal products intended for use in humans as well as requirements for the granting of a license to manufacture or Import of such products.
- Law on the trade in medicinal products ( Medicines Act - AMG). The 14th amendment to the AMG is currently in force. With the amendment by the twelfth law amending the AMG of July 30, 2004, u. a. the Directive 2001/20 / EG implemented (§§ 40 - 42a AMG).
- Ordinance on the application of good clinical practice when conducting clinical trials with medicinal products for use in humans ( GCP Ordinance - GCP-V) dated August 9, 2004.
- Note for Guidance on Good Clinical Practice (CPMP / ICH / 135/95). This guideline of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) describes details of the methodological and technical requirements for clinical trials.
- Investigational preparation : Investigational preparations are dosage forms of active ingredients or placebos that are tested in a clinical trial on humans or used as comparator preparations or used to produce certain reactions in humans. These include drugs that are not approved and approved drugs if they are used in a clinical trial on humans in a dosage form other than the approved one or for a non-approved area of application or to obtain additional information about the approved drug (Section 3 Para . 3 GCP-V).
- Sponsor : A sponsor is a natural or legal person who assumes responsibility for initiating, organizing and financing a clinical trial in humans ( Section 4 (24) AMG).
- Examiner: The examiner is usually a doctor responsible for carrying out the clinical examination on people in a testing center (or, in the case of a dental examination, a dentist) or, in justified exceptional cases, another person whose profession is based on its scientific requirements and how it is carried out Required experience in patient care is qualified to conduct research on humans. The examiner must name at least one deputy with comparable qualifications and nominate qualified members of the checking group. If a clinical trial is carried out by a group of people in a trial site, the investigator is the group leader responsible for carrying out the trial. If a test is carried out in several test centers, the sponsor appoints an investigator as head of the clinical test (LKP) (Section 4 (25) AMG).
- Ethics Committee : The ethics committee is an independent body made up of people working in the health care system and in non-medical areas, whose task it is to ensure the protection of the rights, safety and well-being of persons concerned within the meaning of paragraph 2a and to create public confidence in this regard by it comments on the study plan , the suitability of the investigators and the adequacy of the facilities as well as on the methods used to inform the data subjects and to obtain their informed consent and on the information material used. (§ 3 Paragraph 2c GCP-V).
- Head of the clinical trial (LKP): The GCP guidelines do not provide for the person to be the head of the clinical trial. However, the 12th amendment to the AMG was implemented without foregoing the person of the head of the clinical trial. In the case of multicenter studies, one of the participating investigators should assume the position of director of the clinical trial. In the case of monocentric studies, this is replaced by the examiner from the single study center. In the case of a multi-center study, the management of the study is the responsibility of the head of the clinical trial, and in the case of a single-center study, it is the responsibility of the examiner (Section 40, Paragraph 1, Clause 3, No. 5 AMG). With regard to the qualification of the responsible person according to Section 40, Paragraph 1, Clause 3, No. 5 AMG, the doctor's reservation has been lifted with the 12th amendment to the AMG . At least two years of experience in clinical testing of medicinal products is required .
- First Patient First Visit (FPFV; English for first patient first visit; synonym FSFV; first subject, first visit): the first study participant / patient in a clinical study - time of the first administration of the test drug. Last patient last visit (English for last patient final visit; synonym LSLV; last subject last visit): the last study participant / patient in a clinical study - time of the last visit
Requirement for a clinical trial
The legal requirements for conducting a clinical trial can be found in Sections 40, 41, 42 and 42a of the Medicines Act . As part of the 12th amendment to the AMG, an implicit approval procedure was introduced for the clinical testing of drugs (with the exception of gene transfer drugs, somatic cell therapy drugs and drugs containing genetically modified organisms). The procedure of the approval process is basically as follows:
- Application for a EudraCT number (registration of the clinical trial with the European Medicines Agency (EMA) using a web form). The EudraCT number will be communicated to the applicant by email. The data entered can be printed out for the further approval process.
- Written application for approval of the clinical trial to the competent higher federal authority (in Germany the Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute (PEI)). As a rule, the higher federal authority has 30 days to issue an explicit permit. If there is no notification from the competent higher federal authority within these 30 days, the study is considered approved (Section 42 (2) AMG).
- At the same time, a written application for a positive assessment of the clinical trial must be submitted to the responsible ethics committee in accordance with Section 40 (1) sentence 2 AMG. The assignment of the responsible ethics committee for multi-center studies is based on the position of the head of the clinical trial. The ethics committee responsible for him becomes the so-called responsible ethics committee. Details about the necessary application documents can be found in Section 7 Paragraphs 2 and 3 of the GCP Ordinance. In the case of a multicenter clinical trial, the responsible ethics committee evaluates in consultation with the ethics committees involved. The (local) ethics committees involved check the qualifications of the examiners and the suitability of the inspection bodies in their area of responsibility. The assessment of the local ethics committee must be submitted to the responsible ethics committee within 30 days of receipt of the application (Section 8 (5) GCP-V). In the case of monocentric studies, the ethics committee that is responsible for the main examiner is in charge. If there are several examiners in a test center, one of the examiners becomes the main examiner. The application for a positive evaluation of the clinical trial must be submitted in writing to the ethics committee (Section 7 (1) GCP-V). The ethics committee must confirm receipt of the application to the sponsor within 10 days (Section 8 (1) GCP-V). Within a maximum of 60 days after receipt of a proper application, the responsible ethics committee sends its reasoned assessment to the sponsor and the responsible higher federal authority.
- If both the approval of the competent higher federal authority and an approving assessment by the competent ethics committee have been received, the study can be started after the clinical trial has been reported to the competent authority determined specifically for the federal state (e.g. health department of a district).
Since the application for approval of the clinical trial can be submitted to the competent higher federal authority and the responsible ethics committee at the same time, both institutions evaluate different aspects. The competent higher federal authority primarily checks the quality and safety of the (test) drug. Pharmacological-toxicological and analytical documents as well as clinical data on the test product are relevant for the test. The ethics committee's main focus is on ethical issues and the protection of the test subjects.
During the COVID-19 pandemic , a statutory ordinance of the Federal Ministry of Health was issued in Germany in May 2020 , according to which the lead ethics committee evaluates multi-center clinical studies that serve to prevent or treat COVID-19, and this exceptionally without behavior with the ethics committees involved ( Section 8 (2) MedBVSV). However, this exception only applies until the determination of the epidemic situation of national scope by the Bundestag or until March 31, 2021 at the latest ( Section 5 (4) sentence 1 IfSG).
- Clinical Trials Register
- Jadad scale
- Clinical evaluation
- Primary endpoint
- Secondary endpoint
- Interactive Response Technology
- Trial Master File
- Michael Benesch, Elisabeth Raab-Steiner: Reading and understanding clinical studies . 2nd, updated and revised edition. UTB Facultas, Vienna 2018, ISBN 978-3-8385-4896-8 .
- Sibylle Biefang, Martin A Schreiber, Wolfgang Köpcke: Manual for the planning and implementation of therapy studies . Boarding school Inst. For Scientific Zsarb., Schloss Reisenburg 1981, OCLC 174006101 .
- R., Eberhardt, Ch., Herrlinger, K., Dommisch, S., Kienzle-Horn, A., Völp: Management and monitoring of clinical trials . 7th, revised and updated age 2018 edition. ECV Editio Cantor Verlag for Medicine and Natural Sciences, Aulendorf, ISBN 978-3-87193-459-9 .
- Martin Schumacher, Gabi Schulgen: Methodology of clinical studies. Methodological basics of planning, implementation and evaluation . 3. Edition. Springer-Verlag, Berlin, Heidelberg 2009, ISBN 978-3-540-85136-3 .
- Joachim A. Schwarz, Anja Kerchlango, Gabriele Schwarz, Axel Thiele, Rudolf H. Völler: Guidelines for clinical trials of drugs and medical devices Drug development - Good Clinical Practice - Planning - Organization - Implementation and documentation . 4th, updated and exp. Edition. ECV, Editio-Cantor-Verl, Aulendorf 2011, ISBN 978-3-87193-394-3 .
- Konrad Wink: How do you read and evaluate a clinical study? Schattauer, Stuttgart 2006, ISBN 3-7945-2527-2 .
- WHO International Clinical Trials Registry Platform (ICTRP) Information about the international trial registry network
- German Register of Clinical Studies Search for studies in Germany
- ClinicalTrials.gov database of the National Institutes of Health (USA) - Clinical studies from many countries
- "Clinical trial" information on approval procedures, reporting requirements, definitions, forms, FAQs, etc. on the website of the Federal Institute for Drugs and Medical Devices ( BfArM )
- Declaration of Helsinki (English)
- Codes of Federal Regulation
- 21 CFR Part 11 - Electronic Records; Electronic signatures
- 21 CFR Part 50 - Protection of Human Subjects
- 21 CFR Part 54 - Financial Disclosure by Clinical Investigator
- 21 CFR Part 56 - Institutional Review Board
- 21 CFR Part 312 - Investigational New Drug Application
- 21 CFR Part 314 - Applications for FDA Approval to Market a New Drug
- ↑ a b Bandolier: Clinical trial Archived copy ( Memento of the original from August 18, 2010 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice.
- ↑ a b M. Schumacher, G. Schulgen: Methodology of clinical studies. Methodological basics of planning, implementation and evaluation. 2008.
- ↑ Henrik Kessler: Short textbook medical psychology and sociology . Thieme, 2015, ISBN 978-3-13-152473-7 ( google.de [accessed on August 4, 2015]).
- ↑ time, 2006: pill test http://www.zeit.de/2006/13/M-Pillentest
- ^ H. Kubinyi: Drug research: myths, hype and reality. In: Nat Rev Drug Discov . Vol. 2, 2003, pp. 665-669, PMID 12904816 .
- ^ P. Greaves, A. Williams, M. Eve: First dose of potential new medicines to humans: how animals help. In: Nat Rev Drug Disc. Vol. 3, 2004, pp. 226-236, PMID 15031736 .
- ↑ Co-ordination of Notified Bodies - Medical Devices (NB-MED): Recommendation NB-MED / 2.7 / Rec1 ( Memento of May 6, 2014 in the Internet Archive ) (PDF; 33 kB)
- ↑ Standard DIN EN ISO 14155: 2011 - Clinical testing of medical devices on humans - Good clinical practice 
- ↑ Definition in Directive 2001/20 / EC , Article 2 (e).
- ↑ Implementation in Germany for example through the GCP regulation
- ↑ DAZ Aktuell: 12th AMG amendment: High density of regulations relating to clinical trials , Deutsche Apothekerzeitung 2004, No. 23 of May 30, 2005, p. 24.
- ↑ Gisela Schott: Financing of drug studies by pharmaceutical companies and the consequences - Part 1: Qualitative systematic literature review on the influence on study results, protocol and quality (German), Dtsch Arztebl Int 2010; 107 (16): 279-85 doi: 10.3238 / arztebl.2010.0279 (Engl.)
- ↑ Gisela Schott: Financing of drug studies by pharmaceutical companies and the consequences - Part 2: Qualitative systematic literature review on the influence on authorship, access to study data as well as study registration and publication (German), Dtsch Arztebl Int 2010; 107 (17): 295-301 doi: 10.3238 / arztebl.2010.0295 (Engl.)