Pilot study. Adverse events and clinical outcomes

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

randomized clinical trial in which patients are assigned to treatment groups at random (randomization procedure) and have the same chance of receiving the study or control drug (comparator or placebo). In a non-randomized study, there is no randomization procedure.

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

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

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

prospective study conducted by dividing the participants into groups who would or would not receive the study drug before the outcomes occurred. In contrast to him, in retrospective (historical) study the outcomes of previous clinical trials are being studied, i.e. outcomes occur before the study is started.

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

In a parallel study, two or more groups of subjects are compared, one or more of whom receive an investigational drug and one group is a control. Some parallel studies compare different kinds treatment, without the inclusion of a control group. (This design is called independent group design.)

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

IN case-control study (synonym: case study) compare people with certain disease or outcomes (“case”) with people from the same population who do not have the disease or who did not experience this outcome (“control”), in order to identify the relationship between the outcome and prior exposure to certain risk factors. In a case series study, several individuals are observed, 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 treatment and outcome study in one individual.

Currently, preference is given to the design of a clinical trial of drugs, which provides the most reliable data, for example, when conducting prospective controlled comparative randomized and, preferably, double-blind studies.

IN Lately the role of clinical trials of drugs has increased in connection with the introduction of the principles of evidence-based medicine. Chief among these is making specific clinical decisions for patient care based on the rigorously proven scientific evidence that can be obtained from well-designed, controlled clinical trials.

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

Open and blind clinical study

A clinical trial may be open or blind. open study- this is when both the doctor and his patient know which drug is being investigated. blind study divided into single-blind, double-blind, and full-blind.

Simple blind study is when one party does not know which drug is being investigated.
Double blind study And full blind study is when two or more parties do not have information about the investigational drug.

Pilot Clinical Study is carried out to obtain preliminary data important for planning further stages of the study. On plain language one could call it "sighting". With the help of a pilot study, the possibility of conducting a study on more subjects, the necessary capacities and financial costs for future research are calculated.

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

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

Uncontrolled Clinical Study- this is a study in which there is no group of subjects taking the comparator drug. Typically, this type of clinical trial is conducted for drugs with proven efficacy and safety.

randomized clinical trial is a study in which patients are assigned to several groups (by type of treatment or drug regimen) randomly and have the same opportunity to receive the investigational or control drug (comparator drug or placebo). IN non-randomized study the randomization procedure is not carried out, respectively, patients are not divided into separate groups.

Parallel and crossover clinical trials

Parallel clinical researches - these are studies in which subjects in different groups receive either only the study drug or only the comparator drug. In a parallel study, several groups of subjects are compared, one of which receives the investigational drug, and the other group is the control. Some parallel studies compare different treatments without including a control group.

Crossover Clinical Studies are studies in which each patient receives both drugs compared, in a random sequence.

Prospective and retrospective clinical trial

Prospective Clinical Study- this is the observation of a group of patients for a long time, until the onset of an outcome (a clinically significant event that serves as an object of interest to the researcher - remission, response to treatment, relapse, death). Such a study 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 previous clinical trials are being studied, i.e. outcomes occur before the study has begun.

Single 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, however, the study is conducted in several countries (as a rule, the centers are located in different countries), it is called international.

Cohort Clinical Study is a study in which a selected group (cohort) of participants is observed for some 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, groups of subjects are formed in the present and observed in the future. In a retrospective cohort clinical study, groups of subjects are selected on the basis of archival data and trace their results to the present.

What type of clinical trial would be the most credible?

Recently, pharmaceutical companies are obligated to conduct clinical trials, in which the most reliable data. Most often meets these requirements prospective, double-blind, randomized, multicenter, placebo-controlled study. It means that:

prospective– will be monitored for a long time;
Randomized- patients were randomly assigned to groups (usually this is done by a special computer program, so that in the end 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, so such a study is as objective as possible;
Multicenter- carried out in several institutions at once. Some types of tumors are extremely rare (for example, the presence of an ALK mutation in non-small cell lung cancer), so it is difficult to find in one center required amount patients who meet the inclusion criteria for the protocol. Therefore, such clinical trials are carried out in several research centers, and as a rule, in several countries at the same time they are called international;
placebo controlled– participants are divided into two groups, one receives the study drug, the other receives a placebo;

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

This figure shows the infiltrating Bone marrow lymphocytes in cell culture

The results of the study involving a specific type of tumor-targeting T cell known as marrow-infiltrating lymphocytes (MILs) have been described in the journal Science Translational Medicine.

“What we have learned in this small study is that a large number of activated MILs can selectively target and destroy myeloma cells,” said Ivan Borrello, an immunologist at 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 normal condition they are inactive and too few in number to have a noticeable effect on cancer.

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

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

The scientists isolated MILs from each patient's bone marrow, grew them in the lab to increase their numbers, activated them with microscopic beads coated with immune-activating antibodies, and injected each of the 22 patients intravenously with their own cells. Three days before the introduction of improved 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 that their cancer had been reduced by at least 50%.

Seven patients experienced volume reduction. tumor cells by at least 90% after an average of 25.1 months without cancer progression. The remaining 15 patients had, on average, 11.8 months of disease 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 with less than 90% disease reduction. The mean follow-up time is currently over 6 years.

Dr. Borrello noted that several US cancer centers have conducted a similar experimental treatment known as adoptive T-cell therapy, but said the Johns Hopkins team believe they were the only ones using MILs. He said other types of tumor-infiltrating cells could be used, but they tend to be less numerous 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. “Typically, immune cells from solid tumors, called tumor-infiltrating cells, can be isolated and grown in as few as 25% of patients who could potentially be treated. But in our clinical trial, we were able to isolate and grow MILs in all 22 patients,” said Kimberly Nulan, Ph.D., a research assistant at the Johns Hopkins University School of Medicine.

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

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

Dr. Noonan says the research team has used the 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 has 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 will be in patients. Learning how to improve cell culture can improve treatment,” Dr. Noonan said.

Kimmel Cancer Center scientists have also developed MILs to treat solid tumors such as lung, esophageal, and stomach cancers, 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 US, and more than 10,000 people die from the disease. It is the second most common blood cancer.

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

Search (reconnaissance) research is carried out with the aim of clarifying the problem, more correct formulation of problems and putting forward well-founded hypotheses. Thus, at its core, it is a conceptual study. It is especially desirable to conduct it if there is no literature on the subject of interest to you or it is not enough.

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; the data is not representative. The scientist receives only tentative information about the object of study for a general orientation in the problem. It is used for little studied or not studied problems at all. Its slogan is about, cheap and fast.

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

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

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

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

♦ Object - to conduct both studies, an insignificant set of objects is needed, therefore they are carried out in a limited time frame.

But unlike reconnaissance, a pilot study is designed to work out technical procedures and techniques, most often to test a questionnaire. According to J. Mannheim and R. Rich, a preliminary check of the survey instrument is as important for the success of the study as a test drive is for a successful purchase of a used car. It helps to detect problems that can only fully manifest themselves in the field.

In sociology, aerobatics is carried out before the main study 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 evaluate 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. Piloting is also useful for training a group of interviewers (questionnaires).

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