Pilot study. Adverse events and clinical outcomes

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Pilot study is intended to obtain preliminary data important for planning further stages of the study (determining the possibility of conducting a study with a larger number of subjects, the sample size in a future study, the required power of the study, etc.).

Randomized clinical trial , in which patients are randomly assigned to treatment groups (randomization procedure) and have equal opportunity to receive the study drug or the control drug (comparator or placebo). In a non-randomized study, there is no randomization procedure.

Controlled (sometimes used as a synonym "comparative") clinical trial , in which the studied medicine, the effectiveness and safety of which have not yet been fully studied, is compared with a drug whose effectiveness and safety are well known (comparator drug). This could be a placebo, standard therapy, or no treatment at all. IN uncontrolled (non-comparative) study a control/comparison group (a group of subjects taking a comparison drug) is not used. In more in a broad sense controlled research means any study in which potential sources are controlled (minimized or eliminated if possible) systematic errors(i.e. it is carried out in strict accordance with the protocol, monitored, etc.).

When conducting parallel research subjects in various groups receive either only the study drug or only the comparator/placebo drug. IN cross-sectional studies each patient receives both drugs being compared, usually in random order.

Research can be open when all study participants know which drug the patient is receiving, and blind (disguised) when one (single-blind study) or more parties participating in the study (double-blind, triple-blind or completely blind study) are kept in the dark about the allocation of patients to treatment groups.

Prospective study is conducted by dividing participants into groups that will or will not receive the study drug before the outcomes occur. In contrast to him, in retrospective (historical) study the outcomes of previously conducted clinical studies are studied, i.e. outcomes occur before the study begins.

Depending on the number of research centers in which the study is conducted in accordance with a single protocol, studies can be single-center or multicenter . If a study is conducted in several countries, it is called international.

A parallel study compares two or more groups of subjects, one or more of which receive the study drug and one group is a control. Some parallel studies compare different kinds treatment, without including a control group. (This design is called an independent groups design.)

Cohort study is an observational study in which a selected group of people (cohort) is observed over time. Outcomes of subjects in different subgroups of this cohort, those who were or were not exposed (or were exposed in varying degrees) treatment with the study drug are compared. In a prospective cohort study, cohorts are established in the present and followed in the future. In a retrospective (or historical) cohort study, a cohort is selected from historical records and their outcomes are followed from then to the present.

IN case-control study (synonym: case study) compares people with a certain disease or outcomes (“cases”) with people from the same population who do not have the disease or who did not experience the outcome (“controls”), to identify the relationship between the outcome and prior exposure to specific risk factors. A case series study follows several individuals, usually receiving the same treatment, without the use of a control group. In the case description (synonyms: case report, medical history, description isolated case) is a study of treatment and outcome in one person.

Currently, preference is given to the design of clinical drug trials that provides the most reliable data, for example, by conducting prospective controlled comparative randomized and, preferably, double-blind studies.

IN Lately the role of clinical trials of drugs has increased due to the introduction of principles into practical healthcare evidence-based medicine. And chief among them is making specific clinical decisions for patient treatment based on rigorous scientific evidence that can be obtained through well-designed, controlled clinical trials.

Antitumor drugs differ, each of them is carried out for specific purposes and is selected according to the necessary parameters for studying the drug. On currently allocate the following types clinical studies:

Open and blinded clinical trial

A clinical trial can be open and blind. Open study- this is when both the doctor and his patient know which drug is being studied. Blind study divided into single-blind, double-blind and completely blind.

Single blind study- this is when one party does not know which drug is being studied.
Double blind study And completely blind study is when two or more parties do not have information regarding the study drug.

Pilot clinical trial is carried out to obtain preliminary data important for planning further stages of the study. On in simple language one could call it “sighting.” Using a pilot study, the feasibility of conducting research on more subjects, the required capacity and financial costs for future research are calculated.

Controlled clinical trial- This comparative study, in which a new (investigational) drug, the effectiveness and safety of which has not yet been fully studied, is compared with a standard treatment, that is, a drug that has already been studied and entered the market.

Patients in the first group receive therapy with the study drug, patients in the second receive standard therapy (this group is called control, hence the name of the type of research). The comparator drug can be either standard therapy or placebo.

Uncontrolled clinical trial is a study in which there is no group of subjects taking a comparator drug. Typically, this type of clinical research is carried out for drugs with already proven effectiveness and safety.

Randomized clinical trial is a study in which patients are randomly assigned to several groups (by treatment or drug regimen) and have equal opportunity to receive the study drug or a control drug (comparator or placebo). IN non-randomized study There is no randomization procedure; therefore, patients are not divided into separate groups.

Parallel and crossover clinical trials

Parallel clinical researches are studies in which subjects in different groups receive either only the drug being studied or only a comparison drug. A parallel study compares several groups of subjects, one of which receives the study drug, and the other group is a control. Some parallel studies compare different treatments without including a control group.

Crossover clinical studies are studies in which each patient receives both drugs being compared, in a random order.

Prospective and retrospective clinical study

Prospective clinical study- this is observation of a group of patients for a long time, until the onset of outcome (a clinically significant event that serves as the object of interest of the researcher - remission, response to treatment, relapse, death). Such research is the most reliable and therefore is carried out most often, and in different countries at the same time, in other words, it is international.

Unlike a prospective study, retrospective clinical study On the contrary, the outcomes of previously conducted clinical trials are studied, i.e. outcomes occur before the study begins.

Single-center and multicenter clinical trial

If a clinical trial takes place at a single research center, it is called single-center, and if based on several, then multicenter. If the study is carried out in several countries (as a rule, the centers are located in different countries), it is called international.

Cohort clinical trial is a study in which a selected group (cohort) of participants is observed over a period of time. At the end of this time, the results of the study are compared among subjects in different subgroups of this cohort. Based on these results, a conclusion is drawn.

In a prospective cohort clinical study, subjects are grouped in the present time and followed in the future. In a retrospective cohort clinical study, groups of subjects are selected based on archival data and their results are tracked to the present.

What type of clinical trial will be most reliable?

Recently, pharmaceutical companies have been required to conduct clinical studies in which results are obtained. the most reliable data. Most often it satisfies these requirements prospective, double-blind, randomized, multicenter, placebo-controlled study. It means that:

Prospective– observation will be carried out for a long time;
Randomized– patients were randomly assigned to groups (this is usually done by a special computer program, so that eventually the differences between the groups become insignificant, that is, statistically unreliable);
Double blind- neither the doctor nor the patient knows which group the patient fell into during randomization, therefore such a study is as objective as possible;
Multicenter– performed in several institutions at once. Some tumor types are extremely rare (for example, the presence of an ALK mutation in non-small cell lung cancer), so it is difficult to find in a single center required amount patients meeting protocol inclusion criteria. Therefore, such clinical studies are carried out in several research centers, and as a rule, in several countries at the same time and are called international;
Placebo-controlled– participants are divided into two groups, some receive the study drug, others receive a placebo;

In reporting the first small clinical trial in this area, researchers from cancer center Kimmel University at Johns Hopkins University say they have safely used immune cells grown from patients' own bone marrow to treat multiple myeloma– cancer of white blood cells.

This figure shows infiltrating Bone marrow lymphocytes in cell culture

The results of the study, which involved a specific type of tumor-targeting T cells known as marrow-infiltrating lymphocytes (MILs), were described in the journal Science Translational Medicine.

“What we learned in this small study is that a large number of activated MILs can selectively target and kill myeloma cells,” said immunologist Ivan Borrello of Johns Hopkins University, Dr. medical sciences, who led the clinical trial.

He explained that MILs are foot soldiers immune system and attack foreign cells such as bacteria or viruses. But in his in good condition they are inactive and too few in number to have a noticeable effect on cancer.

Previous laboratory research Dr. Borrello and colleagues showed that activated MILs can selectively target and kill myeloma cells taken from patients and grown in vitro.

For the clinical trial, the team recruited 25 patients with newly diagnosed or relapsed multiple myeloma, although 3 of these patients relapsed before they could receive treatment with MILs.

The scientists isolated MILs from each patient's bone marrow, grew them in the laboratory to increase their numbers, activated them with microscopic beads coated with immune-activating antibodies, and injected them intravenously into each of the 22 patients with their own cells. Three days before receiving enhanced MILs, patients received high doses chemotherapy and stem cell transplantation – standard treatment for multiple myeloma.

One year after treatment with MILs, 13 of 22 patients had at least a partial response to therapy, meaning their cancer had shrunk by at least 50%.

Seven patients had a decrease in volume tumor cells by at least 90%, after an average of 25.1 months without cancer progression. The remaining 15 patients had an average of 11.8 months progression-free time after treatment with MILs. None of the participants had serious side effects from treatment. Overall survival was 31.5 months for those who had less than 90% disease reduction. The average follow-up time is currently more than 6 years.

Dr. Borrello noted that several U.S. cancer centers have conducted a similar experimental treatment known as adoptive T-cell therapy, but said the Johns Hopkins team believes they were the only ones using MILs. He said other types of tumor-infiltrating cells can be used, but they tend to be less abundant in a patient's tumor and may not grow well outside the body.

In tumors like melanoma, only half of patients have T cells in their tumor that can be isolated, and about half of which can be grown. “As a rule, immune cells from solid tumors, called tumor-infiltrating cells, can be isolated and cultured from as few as 25% of patients who would potentially be eligible for treatment. But in our clinical trial, we were able to isolate and grow MILs from all 22 patients,” said Kimberly Nulan, PhD, a postdoctoral fellow at Johns Hopkins University School of Medicine.

Nulan says that a little research helped her and her colleagues learn more about which patients might benefit from treatment with MILs. For example, they were able to determine how many of the lab-grown MILs specifically targeted a patient's tumor and whether they continued to target the tumor after administration.

In addition, scientists found that patients whose bone marrow before treatment contained higher levels of certain immune cells, known as central memory cells, also had a better response to treatment with MILs. Patients who began treatment with signs of an overactive immune response did not respond well to treatment.

Dr. Noonan says the research team used these data to guide two other ongoing clinical trials of MILs. These studies are trying to expand the antitumor response and tumor specificity by combining transplantation of MILs with a cancer vaccine called GVAX, developed at Johns Hopkins University, and the myeloma drug lenalidomide, which stimulates T-cell responses.

The researchers also say the trial also shed light on new ways to grow MILs. “In most of these studies, you see that the more cells you get, the better the response you see in patients. Learning how to grow cells better could improve treatments,” Dr. Noonan said.

Kimmel Cancer Center scientists have also developed MILs to treat solid tumors such as lung, esophageal and gastric cancer, as well as childhood neuroblastoma and Ewing's sarcoma.

Experts report that more than 20,000 cases of multiple myeloma occur each year in the United States, and more than 10,000 people die from the disease. It is the second most common blood cancer.

The term “pilot study” is used in the literature as: 1) a synonym for exploratory (exploratory) research; 2) synonym pilot study; 3) a collective concept that includes both its varieties (subspecies) search (reconnaissance) and pilot research. We will assume that search (reconnaissance) and pilot research are the two main subtypes of trial research.

Exploratory (exploratory) research carried out with the aim of clarifying the problem, more correctly setting tasks and putting forward well-founded hypotheses. Thus, at its core it is conceptual study. Carrying it out is especially desirable if there is no literature on the topic you are interested in or it is insufficient.

Intelligence research is the simplest type of sociological analysis: the range of tasks is limited, the number of respondents is small, the program and tools are extremely simplified; data is not representative. The scientist receives only rough information about the object of research for general orientation in the problem. It is used for little-studied or unstudied problems. His slogan is approximately, cheap and fast.

Exploratory research can be carried out using the following methods: interviews (preferably informal) with potential respondents; observation; focus group on the central research problem; survey of experts - specialists or simply people related to the problem area of interest to you; study of documents, statistical data containing the necessary information on the proposed tasks and hypotheses.

A variant of intelligence research is express surveys. They are also called operational surveys . They are used by numerous survey firms - from VTsIOM to ROMIR. True, they conduct surveys, as a rule, very competently, but they do not set deep scientific tasks for the development of fundamental science. Momentary, but very necessary utilitarian problems for society, a department or a private customer are solved: how people feel about the president, the ban on abortion, the war in Chechnya, the arrival of Bush, the terrorist attacks of September 11, 2001. Thus, they obtain a fresh, short-lived product (its lifespan is calculated in days , weeks, less often months), but very necessary information at the moment.

An exploratory study is often also called a pilot study. Although it is more correct to consider it an independent type of sociological research. Reconnaissance and aerobatic research are similar in two respects:

♦ Purpose - obtain approximate data on a particular phenomenon or test the application of the methodology to larger-scale studies.

♦ Object - to conduct both studies, a small number of objects are needed, so they are carried out in a limited time.

But unlike reconnaissance research, pilot research is intended to test technical procedures and techniques, most often to test a questionnaire. Preliminary testing of survey instruments is as important for the success of the study, according to J. Mannheim and R. Rich, as a test drive is for the successful purchase of a used car. It helps to detect problems that can only fully manifest themselves in the field.

In sociology, piloting is carried out before the main research and acts as a way to test the validity of hypotheses and tasks, as well as the professional level and methodological sophistication of the tools. Piloting helps to assess the correctness of the sampling model and make appropriate corrections to it, if necessary; clarify some characteristics of the object and subject of the study, justify the financial costs and timing of the main study. Aerobatics is also useful for training a group of interviewers (questionnaires).

Piloting is useful for: a) testing tools in which the researcher is quite confident, b) improving tools in a situation where the subject of research is less known to the researcher. In the first case, the toolkit undergoes preliminary testing in its final version. In the second, the researcher may want to experiment with different options (layouts) of the tool to find out which one is more convenient to use.