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The development of a new drug is a really very complicated and long-lasting challenge with numerous researchers involved in it. From the first concept up to the available treatment it takes approximately twelve years.
At the very beginning of the development of a drug so-called targets have to be detected. A target for example may be a protein from which researchers suspect, that it might be involved in the emergence of a certain illness. If such molecules can successfully be stimulated or blocked, it might be possible to soothe or even heal a disease. Concerning this matter pharmaceutical companies have developed gigantic libraries which contain several millions of substances. These substances usually are one by one brought together with the target of interest. This process is called "High Throughput screening".
For being accepted as an active agent, a substance has to fulfill numerous requirements: healing or at least soothing a sickness, it must not affect other molecules in the human body if possible (side effects), it must reach its place of action before being eliminated and last but not least the agent should not be poisonous after multiple overdosages.
An experimental program for the evaluation of an antimycotic drug always consists of numerous steps.
I will introduce an experimental program, which is built up from different single studies, covering both preclinical and clinical experiments. Clinical studies are classified in different phases (I-IV).
In order not to go beyond the scope I will focus on the phase II study, which is the relevant part for evaluating a new drug. Therefore preclinical experiments and phase I, III and IV studies will be presented in terms of a short overwiev. It is important to know, that each experiment is subject to ethical approval and to financial issues (sponsors, grants).
Preclinical experiments in the laboratory: effectiveness and compatibility
Compound X is a substance which is chemically well characterized and appears to have an antimycotic effect. At first this active agent has to be tested in the laboratory on its effectiveness. Different studies concerning tolerance and distribution will be performed. Toxicologists examine with comprehensive security checks, whether Compound X is toxic or not, if it can cause embryopathy or if it is able to trigger cancer or changes of the genome. Besides cell cultures, animals are also required for all these tests, in order to imitate the complex procedure within the living body. This is important being able to recognize possible detrimental effects before applying the substance in man. If Compound X meets demands it may be applied for patent.
Phase I Study:
Now Compound X can be tested for the first time in people. Tolerance of this new drug has to be evaluated. In healthy volunteers it will be checked how small application rates of Compound X behave in the body, and at what concentration it starts to cause side effects. In phase I studies normally some dozens of healthy persons are included. Afterwards the appropriate pharmaceutical form has to be figured out.
Phase II Studien:
Clinical trials are experimental studies which involve people as study units. Clinical trials nowadays play a major role in deciding the efficacy of new substances as they become available. Early investigations of new treatments tend to focus on animal studies, but the ultimate evaluation involves a clinical trial.In modern therapy research controlled studies, in which single persons are assigned to the test arms by random are regarded as a gold standard to provide valid evidence of effectiveness2. Basic idea is to avoid systematic faults by an ideal experimental design and to create the prerequisite for a clear detection of causalities.
Compound X does not show any essential side effects in phase I, therefore it can be applied in larger group of patients (100 to 500), which receive either Compound X or a conventional treatment. In this study efficacy, compatibility and possible interactions with other drugs are being examined.
Representative for all other studies of this experimental program I will present the various steps of phase II in form of a study protocol.
Study Protocol Phase II: Compound X
Introduction / Background
Patients with HIV often present with Candida esophagitis. Drug A is regarded as a first-line treatment.
Compound X belongs to the group of echinocandine. In-vitro activity was shown against Candida spp. at similar M.I.C.
A multicenter, randomised, double-blind, phase II study to investigate the efficacy, safety and tolerability of 1 dose Compound X 50 mg i.v. a day vs drug A 0.6 mg/kg body weight/day for the treatment of endoscopically proven esophageal candidiasis
Superpharma, Berne, Switzerland
Institute for Infectious Diseases, University of Bern (ifik) & local institutes of microbiology
The aim of this study is to demonstrate that Compound X has a better response rate and less side effects compared to drug A
To evaluate and compare the efficacy, safety and tolerability of 1 dose Compound X 50 mg vs drug A 0.6 mg/kg body weight/day for the treatment of endoscopically proven esophageal candidiasis during 14 days
Multicenter, double-blind, randomised, comparing 1 dose of Compound X 50 mg iv vs drug A 0.6 mg/kg body weight / day during 14 days
The study first consists of a screening of patients presenting with symptomatic esophageal candidiasis.
The diagnosis of Candidiasis will be assessed by endoscopy and biopsy before inclusion, randomisation and treatment start.
Esophageal specimens will be collected and processed for microscopy and culture at the local Institute of Microbiology at each visit. This allows for confirmation of diagnosis, quantitative assessment and identification of the fungal species. In vitro susceptibility testing of isolates of yeast will also be conducted.
Screening (visit 1):
Evaluation of signs and symptoms of esophagal candidiasis
Physical examination and vital signs
Laboratory tests: hematology, chemistry
Biospsies will be sent to the local Institute of Microbiology for microscopy and culture.
Randomisation and treatment start
An entry culture should be positive for Candida albicans or one of the other Candida species. Testing should be performed to identify the isolates to species level. Yeast isolates collected at different visits will be specified and tested for in vitro susceptibility.
Post-treatment visit (Visit 2) (test of cure)
Physical examination and vital signs (21-30 days)
Signs and symptoms evaluation
Microscopic examination and culture
For an overview see Table 1
adults (at least 18 yrs old)
Patients who are able to understand
protocol and have given informed consent
endoscopically and microbiologically
documented Candida esophagitis
Patients treated with drug A during the prior 4 weeks
Pregnant or nursing women
Creatinine clearance, aminotransferase levels (3-5x upper limit), anemia
inability to undergo repeat treatment, clinical evaluations, and other diagnostic procedures required by the protocol
Number of Patients / Randomisation
Based on power analysis at least 120 patients presenting with symptomatic esophagal candidiasis randomized in 2 parallel groups. The number of patients randomised will be equal in both groups
Duration of study
Recruitment is expected to start on day X. The clinical phase of this study will take approximately 12 months
Estimated Number of study centers
The study will be conducted in 7 sites in Switzerland
Study Medication Dose/Route/Regimen
Compound X: 50 mg by intravenous infusion once daily during 7-14 days
Drug A: 0.6 mg/kg body weight / day, once daily by intravenous infusion for 7-14 days
Primary endpoint: Overall therapeutic cure rate
Therapeutic cure: A patient who is judged to be both a clinical cure and fungal eradication (day 21 to 30 of the study)
This composite endpoint is made up of the clinical cure rate and the mycological outcome (eradication or persistence) for candidiasis
Overall therapeutic cure rate at visit 2 will be analysed using one-sided Chi-Square-test (x2)
Dose-response relationship will be modeled for each dose group using Emax-model
Clinical cure rate
Time to resolution of symptoms
Eradication or persistence for candidiasis
Secondary endpoints will be analysed using
appropriate statistical methods.
Criteria for Efficacy
Clinical outcome: Cure or improvement/failure
Assessment of efficacy on symptoms of esophagitis
Optionally supported by patient symptom assessment
Cure: resolution of all entry clinical signs and symptoms
worsening of entry signs and symptoms
new signs or symptoms of the disease
need for treatment with additional antimicrobial therapy
Cure: Mycological eradication; negative culture (no growth) for Candida albicans (or baseline yeast pathogen)
Improvement/failure: positive culture for Candida albicans (or baseline yeast pathogen)
Overall therapeutic assessment:
Therapeutic cure: Patient who is considered both a clinical cure and mycological eradication
Therapeutic failure: Patient who anytime during the study period was considered by the investigator as a clinical failure or mycological persistence.
Criteria for Safety
The following safety assessment will be performed:
adverse events (local and systemic)
Safety laboratory tests: hematology, chemistry (Visit 1 & 2)
sample size evaluation: Coumpound X group must be statistically significantly superior to drug A (chi square test). Sample size estimation are performed by NQuery Advisor
The evolution of all (primary and secondary) endpoints will be compared to baseline. All statistical tests will be one-sided at the 5% significance level. 95% confidence intervals of the treatment difference will be presented to illustrate the precision of the study
Compliance with good clinical practice, ethical considerations & informed consent
The study must be conducted in compliance with the independent ethics committee/institutional review board (IEC/IRD)'s recommendation, informed consent regulations, ICH GCP Guidelines3 and this protocol. In addition this study will adhere to all local regulatory requirements and Declaration of Helsinki1.
A written informed consent must be obtained by the investigator for each volunteer participating in the study. This protocol and other documents will be submitted by the investigator to an independent Ethics Committee and the institutional Review Board.
Case report forms
CRF will be implemented by Contract Research Organisation
Study management & materials
The investigator is to record all data with respect to protocol procedures on the case report forms.
Source Data Verification
Source data consists of original records or certified copies necessary for the reconstruction and evaluation of the trial.
Clinical study report
A final clinical study report will be prepared according to the ICH guideline on Structure and Content of clinical study reports (ICH E3).
All measures must be taken in order to insure the patient`s anonymity.
Financing and insurance
A financial agreement will be signed between the investigator and the sponsor, outlining overall sponsor and investigator responsibilities to the study. The agreement should describe the costs for pharmacy, laboratory and other protocol required services and the remuneration needed to be paid