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    Home > Medical News > Latest Medical News > "Proof of concept" is important, putting them into early clinical trials -- a brief look at POC studies.

    "Proof of concept" is important, putting them into early clinical trials -- a brief look at POC studies.

    • Last Update: 2020-07-28
    • Source: Internet
    • Author: User
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    Guide: The guiding principle to see inside but the word beads are never long!On June 2000, the Drug Review Center of the State Drug Administration published the Technical Guidelines for Clinical Trials of Chemical Lycandic New Drugs (Draft for Comments) with a huge amount of informationHas you noticed the word "proof of concept"? A total of secondary drug improvement new drug clinical research and development can learn from the clinical development experience of listed drugs based on clear clinical needs - such as the existing listed drugs to improve the efficacy, toxicity to be improved or the mode of administration to be optimizedConducting the necessary clinical trials is usually a proof of concept in clinical trials and ultimately validation of clinical advantagesSome new drugs for chemical modification may have the potential to explore new indicationsSuch as by optimizing the structure, dosage form or change the mode of administration, such as the development of new indications can draw on the marketed drug clinical trial data on the structure or target known toxicity risk control appropriate simplification of early dose exploration test from the exploration of the new indication of the concept of the proof test in accordance with the general law of the innovation drug development gradually progressive to confirm the benefitsIn order to improve the safety of existing drugs, new drugs should first identify the mechanism of adverse reaction occurrence to be improved - is related to the off-target toxicity of the chemical active ingredient monomer or a toxic metabolites related to the tissue distribution and pharmacokinetic characteristics of the original formulation or with a prescription excipient; The guiding principle to look inside but the word beads are never long! Here's not a false word, but a realistic type of experiment based on the database search found that this type of experiment is only one: since the guide makes clear that should be carried out and actually carried out and so little here, the task of filling today's task is to fill the hole for future "proof-of-concept testing" to pave some cognitive path, "proof of concept" is the beginning or to save money before the research and development ideas: the use of disease animal models to screen the active new entity compounds, Natural compounds However, this model has obvious disadvantages Animal models often can not accurately predict the efficacy of the human body so there are enterprises to the research and development of the target to develop and then according to the target site to design, screen and optimize the new compound entities eventually launched new drugsThe initial advantage of this strategy is very clear that many star products at the end of the last century are based on this idea of successful research and development after the bottleneck of this model began to appear leading to the new compound to market slow down the failure rate increasedData show a trend in the conversion rate from the number of trials at different stages to the drug market: data analysis results show that most new compounds are stagnant in phase trials, the main cause of which is the effectiveness of the drugThe failure of the period certainly means that previous human and financial investments have been lost and the development of ineffective candidate drugs must be reduced on the basis of cost reduction and risk control considerationsSecond, how to reduce the risk of development? Mechanism verification (): The pharmacological effects of the drug can be safely shown in the human body through experimentsIt emphasizes the human body rather than the animal models used in the early stages of developmentProof of Concept (): Means that the pharmacological effects of validation of candidate drugs can be translated into clinical benefits generally conducted at the early clinical study stage (usually they are placed in phase studies) can be performed independently as shown in the following figureClinical efficacy is the long-term effect of pharmacological effects and cumulative results in a target of pharmacological effects may not necessarily be translated into clinical therapeutic effectsFor example, a drug can indeed inhibit a critical step in a disease's metabolic pathway but the metabolic pathways involved in the disease are usually not one and there is a metabolic bypass so that inhibition of key steps of a pathway does not necessarily lead to the desired clinical benefitsAlthough there are literature reports abroad that the new compound entities have completed confirmation during the period and confirmation is very rare in the periodBut from the beginning of wen we in the domestic clinical trial database search results to see at least few people in the country to do it is a trend because this strategy can reduce costs and control risks is also recommended Most of this is completed because there are already some clinical studies at this time that the results of the study are available for reference The easiest way to design a study at this time is to select a dose (maximum tolerable dose) and a placebo to compare the study The risk of continuing the trial without observing the drug efficacy signal (negative) at dose is not normally below the dose or not (except for the type-effect relationship curve) to continue the trial; Third, the trial design period to carry out the test first to select the right disease patients, they most need to have a clear molecular target The choice of target position should take into account factors: each disease is affected by multiple and environmental factors but the target is often only one and the drug activity is the downstream pathway of tuning the target, the drug efficacy and the abnormality of the disease path show a proportional relationship, at a drug exposure dose these patient groups should be homogend in order to obtain positive results as soon as possible in the smaller group in order to obtain positive results as soon as possible, in addition to the enrichment method can also be used to "get" patients with drug effect target The choice of efficacy endpoint in the design to choose a low-variation indicator, which usually means that fewer patients can be selected, and the faster response of the indicator should usually be less than the waiting day Therefore, the chosen endpoint is often a biomarker with a neutral and high correlation of clinical efficacy, which can speed up the progress of the trial Dutch clinical pharmacologists have concluded the decision-making on whether candidate drugs continue to be tested: the level of exposure of drugs at the target level, the level of drug occupation to the target, and the functional effects of drug action on the target He believes that if this is met, the candidate drug development is the highest chance of success The above and if the occurrence of an equivalent to a positive situation occurs is equivalent to a positive signal Four, seem to have known the feeling? The relationship between the various proper nounabbies in drug development is well-known if some terms overlap or a subset of a noun is a bit similar to a clinical early-stage study or as part of a study you understand it Of course, there is a difference between subsets and parent sets The main biomarkers selected are related to the mechanism of action of candidate molecules, and the selection of downstream biomarkers related to clinical efficacy is selected as an indicator In addition, the methods that can be modeled and simulated are carried out and are usually solid studies that do not model and simulate There are exceptions to everything we'll see below V To give a real chestnut example: The study we designed in the project's phase study included peripheral blood cell surface receptor occupancy 、、、 and biomarkers、、、 such as radon and other biomarkers; Second, let's look at a chestnut that looked beautiful early and ultimately failed Humanized monoclonal antibody bone bridge protein is considered to be a target related to pathogenesis In addition to safety, tolerance and research, the researchers found that the content of bone bridge protein complex in the body was proportional to the dose, which was positive However, in the patient's study, the study was observed with commonly used efficacy indicators and found no significant difference snobbery between the drug and the placebo group That is to say, bone bridge protein as a new target for the treatment may have problems Finally, a recent, successful chestnut-announced phase-proofing study assessed the safety, tolerance, pharmacomaticandism, and efficacy of a controlled drug (adamu singa), to moderate and severe patients with inadequate response The proof-of-concept indicator used in this study is the assessment time is weeks (slightly longer but in line with the characteristics of clinical efficacy indicators) The study also has a significant feature of breaking and not using the practice of simulated virtual studies in their design to select Adamu monoto-resistance historical data to supplement the adamu monoto-resistance test data and comparative analysis This is designed to save samples and time by using a virtual combination Based on this study, virtual data and even simulation methods for future clinical trial history data could be used in the study References: Wei Minji Zhao Deheng's advance thinking for early clinical research on new drugs - from mechanism verification to proof-of-concept China New Drug Journal
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