Clinical Trials News

Statistics in Medicine — Reporting of Subgroup Analyses in Clinical Trials

2007-11-22T15:07:00.000-08:00

Medical research relies on clinical trials to assess therapeutic benefits. Because of the effort and cost involved in these studies, investigators frequently use analyses of subgroups of study participants to extract as much information as possible. Such analyses, which assess the heterogeneity of treatment effects in subgroups of patients, may provide useful information for the care of patients and for future research. However, subgroup analyses also introduce analytic challenges and can lead to overstated and misleading results. This report outlines the challenges associated with conducting and reporting subgroup analyses, and it sets forth guidelines for their use in the Journal. Although this report focuses on the reporting of clinical trials, many of the issues discussed also apply to observational studies.

Subgroup Analysis

By "subgroup analysis," we mean any evaluation of treatment effects for a specific end point in subgroups of patients defined by baseline characteristics. The end point may be a measure of treatment efficacy or safety. For a given end point, the treatment effect — a comparison between the treatment groups — is typically measured by a relative risk, odds ratio, or arithmetic difference. The research question usually posed is this: Do the treatment effects vary among the levels of a baseline factor?

A subgroup analysis is sometimes undertaken to assess treatment effects for a specific patient characteristic; this assessment is often listed as a primary or secondary study objective. For example, Sacks et al.8 conducted a placebo-controlled trial in which the reduction in the incidence of coronary events with the use of pravastatin was examined in a diverse population of persons who had survived a myocardial infarction. In subgroup analyses, the investigators further examined whether the efficacy of pravastatin relative to placebo in preventing coronary events varied according to the patients' baseline low-density lipoprotein (LDL) levels.

Subgroup analyses are also undertaken to investigate the consistency of the trial conclusions among different subpopulations defined by each of multiple baseline characteristics of the patients. For example, Jackson et al.9 reported the outcomes of a study in which 36,282 postmenopausal women 50 to 79 years of age were randomly assigned to receive 1000 mg of elemental calcium with 400 IU of vitamin D3 daily or placebo. Fractures, the primary outcome, were ascertained over an average follow-up period of 7.0 years; bone density was a secondary outcome. Overall, no treatment effect was found for the primary outcome; that is, the active treatment was not shown to prevent fractures. The effect of calcium plus vitamin D supplementation relative to placebo on the risk of each of four fracture outcomes was further analyzed for consistency in subgroups defined by 15 characteristics of the participants.

Heterogeneity and Statistical Interactions

The heterogeneity of treatment effects across the levels of a baseline variable refers to the circumstance in which the treatment effects vary across the levels of the baseline characteristic. Heterogeneity is sometimes further classified as being either quantitative or qualitative. In the first case, one treatment is always better than the other, but by various degrees, whereas in the second case, one treatment is better than the other for one subgroup of patients and worse than the other for another subgroup of patients. Such variation, also called "effect modification," is typically expressed in a statistical model as an interaction term or terms between the treatment group and the baseline variable. The presence or absence of interaction is specific to the measure of the treatment effect.

The appropriate statistical method for assessing the heterogeneity of treatment effects among the levels of a baseline variable begins with a statistical test for interaction.10,11,12,13 For example, Sacks et al.8 showed the heterogeneity in pravastatin efficacy by reporting a statistically significant (P=0.03) result of testing for the interaction between the treatment and baseline LDL level when the measure of the treatment effect was the relative risk. Many trials lack the power to detect heterogeneity in treatment effect; thus, the inability to find significant interactions does not show that the treatment effect seen overall necessarily applies to all subjects. A common mistake is to claim heterogeneity on the basis of separate tests of treatment effects within each of the levels of the baseline variable.6,7,14 For example, testing the hypothesis that there is no treatment effect in women and then testing it separately in men does not address the question of whether treatment differences vary according to sex. Another common error is to claim heterogeneity on the basis of the observed treatment-effect sizes within each subgroup, ignoring the uncertainty of these estimates.

Multiplicity

It is common practice to conduct a subgroup analysis for each of several — and often many — baseline characteristics, for each of several end points, or for both. For example, the analysis by Jackson and colleagues9 of the effect of calcium plus vitamin D supplementation relative to placebo on the risk of each of four fracture outcomes for 15 participant characteristics resulted in a total of 60 subgroup analyses.

When multiple subgroup analyses are performed, the probability of a false positive finding can be substantial.7 For example, if the null hypothesis is true for each of 10 independent tests for interaction at the 0.05 significance level, the chance of at least one false positive result exceeds 40%. Thus, one must be cautious in the interpretation of such results. There are several methods for addressing multiplicity that are based on the use of more stringent criteria for statistical significance than the customary P<0.05.7,15 A less formal approach for addressing multiplicity is to note the number of nominally significant interaction tests that would be expected to occur by chance alone. For example, after noting that 60 subgroup analyses were planned, Jackson et al.9 pointed out that "Up to three statistically significant interaction tests (P<0.05) would be expected on the basis of chance alone," and then they incorporated this consideration in their interpretation of the results.

Prespecified Analysis versus Post Hoc Analysis

A prespecified subgroup analysis is one that is planned and documented before any examination of the data, preferably in the study protocol. This analysis includes specification of the end point, the baseline characteristic, and the statistical method used to test for an interaction. For example, the Heart Outcomes Prevention Evaluation 2 investigators16 conducted a study involving 5522 patients with vascular disease or diabetes to assess the effect of homocysteine lowering with folic acid and B vitamins on the risk of a major cardiovascular event. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. In the Methods section of their article, the authors noted that "Prespecified subgroup analyses involving Cox models were used to evaluate outcomes in patients from regions with folate fortification of food and regions without folate fortification, according to the baseline plasma homocysteine level and the baseline serum creatinine level." Post hoc analyses refer to those in which the hypotheses being tested are not specified before any examination of the data. Such analyses are of particular concern because it is often unclear how many were undertaken and whether some were motivated by inspection of the data. However, both prespecified and post hoc subgroup analyses are subject to inflated false positive rates arising from multiple testing. Investigators should avoid the tendency to prespecify many subgroup analyses in the mistaken belief that these analyses are free of the multiplicity problem.

Subgroup Analyses in the Journal — Assessment of Reporting Practices

As part of internal quality-control activities at the Journal, we assessed the completeness and quality of subgroup analyses reported in the Journal during the period from July 1, 2005, through June 30, 2006. A detailed description of the study methods can be found in the Supplementary Appendix, available with the full text of this article at www.nejm.org. In this report, we describe the clarity and completeness of subgroup-analysis reporting, evaluate the authors' interpretation and justification of the results of subgroup analyses, and recommend guidelines for reporting subgroup analyses.

Among the original articles published in the Journal during the period from July 1, 2005, through June 30, 2006, a total of 95 articles reported primary outcome results from randomized clinical trials. Among these 95 articles, 93 reported results from one clinical trial; the remaining 2 articles reported results from two trials. Thus, results from 97 trials were reported, from which subgroup analyses were reported for 59 trials (61%). Table 1 summarizes the characteristics of the trials. We found that larger trials and multicenter trials were significantly more likely to report subgroup analyses than smaller trials and single-center trials, respectively. With the use of multivariate logistic-regression models, when ranked according to the number of participants enrolled in a trial and compared with trials with the fewest participants, the odds ratio for reporting subgroup analyses for the second quartile was 1.38 (95% confidence interval [CI], 0.45 to 4.20), for the third quartile was 1.98 (95% CI, 0.62 to 6.24), and for the fourth quartile was 8.90 (95% CI, 2.10 to 37.78) (P=0.02, trend test). The odds ratio for reporting subgroup analyses in multicenter trials as compared with single-center trials was 4.33 (95% CI, 1.56 to 12.16).Among the 59 trials that reported subgroup analyses, these analyses were mentioned in the Methods section for 21 trials (36%), in the Results section for 57 trials (97%), and in the Discussion section for 37 trials (63%); subgroup analyses were reported in both the text and a figure or table for 39 trials (66%). Other characteristics of the reports are shown in Figure 1. In general, we are unable to determine the number of subgroup analyses conducted; we attempted to count the number of subgroup analyses reported in the article and found that this number was unclear in nine articles (15%). For example, Lees et al.17 reported that "We explored analyses of numerous other subgroups to assess the effect of baseline prognostic factors or coexisting conditions on the treatment effect but found no evidence of nominal significance for any biologically likely factor." For four of these nine articles, we were able to determine that at least eight subgroup analyses were reported. In 40 trials (68%), it was unclear whether any of the subgroup analyses were prespecified or post hoc, and in 3 others (5%) it was unclear whether some were prespecified or post hoc. Interaction tests were reported to have been used to assess the heterogeneity of treatment effects for all subgroup analyses in only 16 trials (27%), and they were reported to be used for some, but not all, subgroup analyses in 11 trials (19%).Analysis of Our Findings and Guidelines for Reporting Subgroups

In the 1-year period studied, the reporting of subgroup analyses was neither uniform nor complete. Because the design of future clinical trials can depend on the results of subgroup analyses, uniformity in reporting would strengthen the foundation on which such research is built. Furthermore, uniformity of reporting will be of value in the interval between recognition of a potential subgroup effect and the availability of adequate data on which to base clinical decisions.

Problems in the reporting of subgroup analyses are not new. Assmann et al reported shortcomings of subgroup analyses in a review of the results of 50 trials published in 1997 in four leading medical journals. More recently, Hernández et al.4 reviewed the results of 63 cardiovascular trials published in 2002 and 2004 and noted the same problems. To improve the quality of reports of parallel-group randomized trials, the Consolidated Standards of Reporting Trials statement was proposed in the mid-1990s and revised in 2001.19 Although there has been considerable discussion of the potential problems associated with subgroup analysis and recommendations on when and how subgroup analyses should be conducted and reported,19,20 our analysis of recent articles shows that problems and ambiguities persist in articles published in the Journal. For example, we found that in about two thirds of the published trials, it was unclear whether any of the reported subgroup analyses were prespecified or post hoc. In more than half of the trials, it was unclear whether interaction tests were used, and in about one third of the trials, within-level results were not presented in a consistent way.

When properly planned, reported, and interpreted, subgroup analyses can provide valuable information. With the availability of Web supplements, the opportunity exists to present more detailed information about the results of a trial. The purpose of the guidelines (see Guidelines for Reporting Subgroup Analysis) is to encourage more clear and complete reporting of subgroup analyses. In some settings, a trial is conducted with a subgroup analysis as one of the primary objectives. These guidelines are directly applicable to the reporting of subgroup analyses in the primary publication of a clinical trial when the subgroup analyses are not among the primary objectives. In other settings, including observational studies, we encourage complete and thorough reporting of the subgroup analyses in the spirit of the guidelines listed.

The editors and statistical consultants of the Journal consider these guidelines to be important in the reporting of subgroup analyses. The goal is to provide transparency in the statistical methods used in order to increase the clarity and completeness of the information reported. As always, these are guidelines and not rules; additions and exemptions can be made as long as there is a clear case for such action.

Guidelines for Reporting Subgroup Analysis.

In the Abstract:

Present subgroup results in the Abstract only if the subgroup analyses were based on a primary study outcome, if they were prespecified, and if they were interpreted in light of the totality of prespecified subgroup analyses undertaken.

In the Methods section:

Indicate the number of prespecified subgroup analyses that were performed and the number of prespecified subgroup analyses that are reported. Distinguish a specific subgroup analysis of special interest, such as that in the article by Sacks et al.,8 from the multiple subgroup analyses typically done to assess the consistency of a treatment effect among various patient characteristics, such as those in the article by Jackson et al.9 For each reported analysis, indicate the end point that was assessed and the statistical method that was used to assess the heterogeneity of treatment differences.

Indicate the number of post hoc subgroup analyses that were performed and the number of post hoc subgroup analyses that are reported. For each reported analysis, indicate the end point that was assessed and the statistical method used to assess the heterogeneity of treatment differences. Detailed descriptions may require a supplementary appendix.

Indicate the potential effect on type I errors (false positives) due to multiple subgroup analyses and how this effect is addressed. If formal adjustments for multiplicity were used, describe them; if no formal adjustment was made, indicate the magnitude of the problem informally, as done by Jackson et al.9

In the Results section:

When possible, base analyses of the heterogeneity of treatment effects on tests for interaction, and present them along with effect estimates (including confidence intervals) within each level of each baseline covariate analyzed. A forest plot21,22 is an effective method for presenting this information.

In the Discussion section:

Avoid overinterpretation of subgroup differences. Be properly cautious in appraising their credibility, acknowledge the limitations, and provide supporting or contradictory data from other studies, if any.
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Chapter 2.3. Type of study and general design

2007-08-08T14:06:00.000-07:00

From the point of view of the knowledge that the doctor and the patient they have about the medication that is receiving the patient distinguish the open studies and the blind studies. In the open studies as much the investigator as the patient knows the treatment that receives the patient. Usually they are opened to the studies of prolonged acceptability and tolerance, the studies made in rare or incurables diseases, the studies badly designed and the farmacocinéticas studies. Blind person means ignorance of the identity of the treatment that is received. The blindness is used to eliminate all those subjective factors, as much on the part of the investigator as of the patient, that can bring confusion at the time of interpreting the results of a treatment in study. The blind studies are classified as well in: , 1) Simple blind person, the doctor knows the treatment that receives the patient but the patient does not know it 2) Double blind person neither the investigator nor the patient know the treatment that receives the patient , 3) Triple blind person neither the patient, nor the investigator nor the patrocinante know the assigned treatment the patients In order to establish causality, that is to say, to be able to affirm that a drug produces a certain effect or is superior to another drug, it is necessary to carry out controlled, randomized and blind studies. This type of design as much provides protection against the slant in the allocation on the part of the investigator and the slant in the evaluation of results by the investigator as by the patient. According to the number of measurements that are made of the variable in study the design can be cross-sectional or longitudinal. In the cross-sectional studies the variables in study are moderate a single time, that is to say, that register diverse characteristics of the population in study in a while determined, as if it was a photography of that population. Soon it is examined if some association between the observed characteristics exists. For example, in a certain population data can be gathered on weight, height, numbers of cholesterol and habit to smoke. Through this design it is possible to be determined if there is association between the different variables, but as the temporary sequence is not known the events, cause cannot be established/effect that is causality. In general, the cross-sectional designs are used for studies of biological processes that are carried out within the laboratories, for diagnosis and stratification (normal ranks), for description of diseases and studies of dose (phase I and 11). In the longitudinal design the evolution in the time of the variables in study is evaluated. Most of the studies in which there is an external intervention and are wanted to establish causality are longitudinal. Although frequently a cross-sectional design is more expeditious, the longitudinal design offers better information generally.

We'll use your suggestion to improve translation quality in future updates to our system.		From the point of view of the knowledge that the doctor and the patient they have about the medication that is receiving the patient distinguish the open studies and the blind studies. In the open studies as much the investigator as the patient knows the treatment that receives the patient. Usually they are opened to the studies of prolonged acceptability and tolerance, the studies made in rare or incurables diseases, the studies badly designed and the farmacocinéticas studies. Blind person means ignorance of the identity of the treatment that is received. The blindness is used to eliminate all those subjective factors, as much on the part of the investigator as of the patient, that can bring confusion at the time of interpreting the results of a treatment in study. The blind studies are classified as well in: , 1) Simple blind person, the doctor knows the treatment that receives the patient but the patient does not know it 2) Double blind person neither the investigator nor the patient know the treatment that receives the patient , 3) Triple blind person neither the patient, nor the investigator nor the patrocinante know the assigned treatment the patients In order to establish causality, that is to say, to be able to affirm that a drug produces a certain effect or is superior to another drug, it is necessary to carry out controlled, randomized and blind studies. This type of design as much provides protection against the slant in the allocation on the part of the investigator and the slant in the evaluation of results by the investigator as by the patient. According to the number of measurements that are made of the variable in study the design can be cross-sectional or longitudinal. In the cross-sectional studies the variables in study are moderate a single time, that is to say, that register diverse characteristics of the population in study in a while determined, as if it was a photography of that population. Soon it is examined if some association between the observed characteristics exists. For example, in a certain population data can be gathered on weight, height, numbers of cholesterol and habit to smoke. Through this design it is possible to be determined if there is association between the different variables, but as the temporary sequence is not known the events, cause cannot be established/effect that is causality. In general, the cross-sectional designs are used for studies of biological processes that are carried out within the laboratories, for diagnosis and stratification (normal ranks), for description of diseases and studies of dose (phase I and 11). In the longitudinal design the evolution in the time of the variables in study is evaluated. Most of the studies in which there is an external intervention and are wanted to establish causality are longitudinal. Although frequently a cross-sectional design is more expeditious, the longitudinal design offers better information generally.

Chapter 2.2. Type of study and general design

2007-07-24T13:53:00.000-07:00

The design of an investigation study is the general plan of the investigator to obtain the answer to a raised question, that is to verify the investigation hypothesis. The selection of the type of design depends on the objective of the study, the resources on which count the investigator, the scope where to the results and the ethical requirements will be applied. All clinical test is based on the experimental method. The objective of this type of studies is to so obtain data on way medicines that it is possible to evaluate and to compare his effectiveness and security in one or more groups of individuals. In the studies that are carried out in a group of patients to those who he himself drug is administered to them, can be established criteria to change a medicine by another one or to change the doses (studies of phase I and 11) and of this form to evaluate the differences between different drugs or different doses from a same drug. Generally in the pharmacoclinics studies two or more groups of compare themselves to whom different treatments are administered to them. The simplest design consists of two groups of patients, a group that receives the drug in investigation and another group that receives placebo or the best one of the treatments available for the disease in study. The results of both treatments are compared and the differences settle down. The allocation of the treatments to each one of the groups is made in randomized form, that is at random. This means that the volunteers can be assigned at random to a group of treatment by means of numbers generated by a computer, applying a table of random numbers or, simply, removing the names from a hat. Of this form it is avoided that the subjectivity of the investigator takes part in the process of allocation of the treatments to the patients and allows that each patient counts on the same possibilities of being assigned to one or another group of treatment. Therefore, it can be assumed that the identified factors that can take to confusion are not identical in both groups and that the groups only defer to each other in which concerns the drug in investigation. If the allocation of treatments is not made in randomized form (for example when it is assigned according to the date of birth, number of clinical history of the patient, day from the visit to the doctor's office, availability of bed or another strategy that allows the investigator to know the allocation before obtaining the consent of the patient) can happen a misalignment in the allocation of treatments and take place a slant. Slant to the confusion or involuntary alterations in the results of a study is denominated. The controlled studies include a called group of reference group control. The group control is a group of patients to whom a treatment is administered to him against which they compare so much the effectiveness as the security of the new drug in study. The existence of the group control allows to compare, to establish causality and statistical meaning. The election of the group control is fundamental. Ideally all clinical test must have a group placebo (medication that does not contain any active drug) like control since it allows to the unequivocal demonstration of the effectiveness and security of a medicine. Nevertheless, for ethical reasons, due to the existence of treatments for most of the diseases, not always placebo in the group is used control. - The group control can be:

1)Placebo .

2)Active Comparator or medicine pattern, is the best existing treatment until the moment for the disease in study .

3)Historical Control, are registries of answers to devices or obtained drugs before an investigation study begins. The historical control only must be used in exceptional cases, like very rare diseases, that they do not allow reuniting a sufficient number of patients or for the drug study that is used in the treatment of lethal diseases like cancer or AIDS.

Chapter 2.1.Clinical research protocol..Methodology

2007-07-17T12:38:00.000-07:00

Methodology:

In this section, I will describe in detailed :

l) The variables that will be evaluated in each clinical study and the form to measure them.

2) The design of the study .

3) Techniques and procedures that are going away to use to reach the proposed objectives.

4) The procedures to safeguard the security of the patients during the study and when finalizing his participation.

1) The variables:

In a clinical study the characteristic to study is named variable.

For example, when the effects of a drug study on the arterial pressure, the values of arterial pressure are the variable in study. We can say that the variables are properties that are not equal in all the individuals but that, like the name say, vary from an individual to another one.

It is sufficient that between different individuals from a population, a property can admit 2 possibilities (values) different so that at least it is considered variable. For example, if the population of the study is “men and women with slight arterial hypertension not treated” the property sex, it is a variable because it can at least adopt 2 different values.

But if the population of the study is “women with slight arterial hypertension treated” the property sex does transform itself into constant because there is no more two different properties and it stops being a variable.

When the variable describes the intervention made by the investigator and the cause of a certain action is considered denominates independent variable. The variable that it describes the result produced by the intervention it denominates dependent.

For example, we suppose that we want to study the factors of risk of anti-inflammatory the secondary digestive hemorrhage to the nonsteroid administration. In this example the investigator administers anti-inflammatory to the patients. The consumption of anti-inflammatory (dose, time of administration) is the independent variable. The appearance of digestive hemorrhage (if it appears) is the dependent variable of the received medication. The variables can be classified in:

,/Variable in study: those on which information in the study looks for and can be deduced of the specific objectives. For example the digestive hemorrhage in the previous example.

,/Variable irrelevant: those that do not have relation with the problem in study. For example the color of eyes of the individuals that participate in 16 clinical study of the previous example .

/Variable to control: those that without being the variables in study, have relation with the created problem and can modify the results of the investigation. For example, in the mentioned study, above the patients who take medicines that also act on the gastric mucosa or protecting it or damaging it .

Once defined the variables in study he must determine itself that measurement scales will be used to measure them, that is that assigns a value to them. The possible values can be numbers or names. The variables are denominated quantitative when they are moderate with representative fractions because the values are numbers that maintain an order and a magnitude and mathematical operations like adding can be made with them, reducing, to multiply or to divide As examples of numerical variables we can mention the values of arterial pressure or the values of hemoglobin.

The variables are called ordinal when the possible values follow a sequence that goes of greater to minor (or vice versa). The ordinal variables can be names (hipoglucemia slight, moderate or severe) or numbers (degree IV of Cardiac Insufficiency determined by the NYHA). The qualitative variables are those that are moderate with nominal or categorical scales because the values are names for example sex or race. The measurement scale that will be used for a variable determines the person who designs the protocol and depends on the precision whereupon she is needed to measure variable happiness based on the design of the study and the availability of the suitable instrument. For example, an investigator can decide to measure the variable glucemia in mg/I, being a this quantitative variable. But, if for the study that carries out, as much detail is not necessary and wants to only register if the individuals are hiperglucémicos severe or no, changes the measurement scale to noun and the variable will be qualitative. It is important to consider that if a variable can be measured in a quantitative scale must become this way, since when choosing a nominal scale loses information.

Chapter 2.0.Clinical Research Protocol .

2007-06-04T14:21:00.000-07:00

With this post begins the chapter 2. It´s about the clinical research protocol.

The protocol is a methodologist and administrative document where all the necessary information for the execution of an investigation is. In fact the protocol is the “handbook of operations” of all investigation.

TITLE OF THE INVESTIGATION

It must be short, precise and concise, leaving in clear the population to study, drugs to use (way of administration and dose), the primary target of the study and the principals variables to evaluate to arrive at that objective. If it is possible, in the title the design would have to be included. The title is the latest that must be written in a protocol and must be prepared to catch the attention of the reader.
Example: International, multicentric, stratified, randomized, double study blind person, with overload of placebo, in parallel groups (design) of gastrointestinal clinical security (variable to measure) of 48 weeks, to demonstrate more that (48 mg/day) (drug of the study) reduces the risk of developing complicated ulcers compared with 500 twice YYYYY mg per day (primary target and comparator) in patients with arthritis of hand of 65 years or (population).

BACKGROUND, RATIONALITY, JUSTIFICATION AND USE OF THE RESULTS

It describes the scientific antecedents related to the created problem and its resolution, obtained after an exhaustive bibliographical revision. It details the type of knowledge that is considered to obtain and the purpose that persecutes in terms of its application and its relation yet the well-known until the moment on the subject. Justification, that can be written as it leaves from I raise of the problem, must offer a convincing argument of which the generated knowledge is useful, applicable and has theoretical, methodological, social or practical value or. In this point the following questions are due to respond: How is related the investigation to the priorities of the disease in study and the effective treatments if it is that there are them? What knowledge and information are had on the subject? What information lacks and is desired to obtain on the base of the already existing thing? Which is the purpose that is persecuted with the knowledge that will offer the study? How will be scattered the results? How will be used the results and who will be the beneficiaries? SUMMARY It must give a clear idea, on which it is the central question that is tried to respond with the study of investigation and its justification. The hypotheses and the objectives of the investigation are due to mention. Also, the summary must contain a brief description of the population, the design, the methods and the procedures of the study.

EXPOSITION OF THE PROBLEM AND HYPOTHESIS

All investigation arises from a problem. The work hypothesis is the provisory answer that sets out to the problem that has considered and which is due to put under verification to see if it can be accepted like valid or be rejected. the hypothesis of a work is the key of the experimental design. A good hypothesis must have the following characteristics: 1) To be think in the planning of the study, not after the results are obtained. 2) To be logical, on the consistent fact that it wants to explain and with confirmed previous hypotheses. 3) To be simple and specific. 4) To be plausible of experimental contrast, that is that can on approval be put under, it can be expressed statistically and it must be able explain or predictive.

OBJECTIVES OF THE STUDY

They are the actions that will be carried out to prove the veracity of the raised hypothesis. The objectives must be necessary, enunciate what is expected of the study and be in context with the hypothesis. Many classifications of the objectives exist: specific, primary and secondary generals and, etc. In general one defines them after to have elaborated the theoretical foundation and to know clearly the sequence between the central question and the possible answers to the question and/or hypothesis of work. . General mission: he is the one that specifies what it is hoped to obtain with the study in knowledge terms. It gives a clear notion of which it is tried to describe, to determine, to identify, to compare and to verify. Example: “To verify that the drug To is as effective as drug B in the treatment of the Isolated 5istólica Hypertension in greater patients of 65 years and that has better tolerance”. Specific objectives: they are those that arise from the decomposition and the logical sequence of the general mission. They are an advance payment of the design of the investigation. Of his analysis it can: to identify population of study, to classify problem (that is to say, to determine if it is of quantification or relation of variables that is comparison/correlation) and to identify or the variables of the study (properties on which information is looking for) Examples of secondary targets for the mentioned primary objective above: . To determine the percentage of reduction of the arterial pressure after four weeks of treatment in both groups, that is the patients who take the medication To and those that take medication B 2. To consider the incidence of orthostatic hypotension in both groups, that is 105 patients who take the medication To and 105 that they take the B. To identify the incidence from adverse effects in both therapeutic groups

POPULATION OF STUDY I I

She is that on which they are wanted to apply the results of an investigation. Objective or white population is called because at her they point the conclusions of the investigation. The population of the study is characterized by the criteria of inclusion and exclusion of the investigation subjects. The inclusion criteria are characteristic specific that defines the white population. They can be more or less restrictive according to the objectives of the study. When stricter they are the criteria of inclusion of a clinical study the studied population will be more homogenous. This homogeneity, will facilitate the detection of differences between the drugs that study, in case they exist. Nevertheless, he will be more difficult extrapolar the results from the study to the general population that is much more heterogeneous. When the criteria of inclusion of a clinical study are ampler, the studied population will be more heterogeneous, therefore it is going to be more difficult to establish differences between the drugs that are studying. But, the conclusions of the clinical study will be able to be applied to a population of ampler reference. Let us see the differences between strict or ample criteria of inclusion in the following examples: the 1) anti-inflammatory clinical study To compares the effectiveness of two nonsteroids in patients who have pains you will articulate by rheumatoid arthritis. The population of the east study is patient with pain to articulate and rheumatoid arthritis (strict criterion). The patients with rheumatoid arthritis will react to studied drugs of similar way allowing one better evaluation of their effectiveness. But, the results of this investigation will be able to be applied only to patients who suffer pain to articulate by rheumatoid arthritis (similar to the population of the study) but will not be able to extrapolate themselves to patients with pains you will articulate caused by other pathologies ( osteoarthitis, etc). 2) anti-inflammatory clinical study 8 compares the effectiveness of two nonsteroids in patients who have pains you will articulate of different etiology (osteoarthitis, rheumatoid arthritis, trauma, etc). The population of the east study is patient with pain to articulate caused by different diseases or problems (wide criteria) that will react of way very different from studied drugs depending on the base disease. Nevertheless, the “results of this investigation will be able to be applied to all the patients with pain to articulate, population that approaches which we called general population. The exclusion criteria are characteristic specific that determines that the individuals cannot be including in a certain study of investigation. As the inclusion criteria the degree of laxitud of such affects to the homogeneity of the studied sample and the external validity of the study. The exclusion criteria allow: 1) To control variables that can confuse during the evaluation of the result of a certain study. 2) To give preeminence to the ethical aspects of the clinical investigation when leaving outside the clinical tests to individuals with the intention of protecting them. Some individuals that they want to participate in a clinical study like investigation subjects, can have a risk greater than the general population of the study by: to be carrying of certain diseases or to be treatment with certain drugs that harness the collateral effects of drugs in study, to present specific contraindications to some of the treatments of the study.

Chapter 1.3. Introduction to clinical trials. Phase IV , Beta error, Planning a Trial

2007-05-25T13:15:00.000-07:00

There is another type of error that can be generated in these studies and that are not to realize that one . We called error beta to the highest probability of not recognizing a difference between treatments that in fact exists. This point is very serious since it implies that it would be let pass an authentic discovery valuable, because was not evaluated tediously it. Worse still, if the investigator is a respected person could happen that the product was discarded for the use in human beings even being the best one. The error beta is equivalent to a false negative. One wanted to very run a risk under “not seeing” a valuable product, but the problem is great since to lower the risk (to reduce to the error beta) it is necessary to incorporate a very high number of patients. In the best international tests, the value beta is of 0,10 (10%), and in many occasions it is of 0,20 (20%). In the present state of things we are defended up to four times more of a false finding (alfa= 0,05) that of not seeing an authentic finding (beta = 0,20).

For all “negative” study it deserves to determine the “statistical power” of the study, that is the possibility of seeing a difference between the obtained results when comparing treatments in clinical studies. The statistical power is defined as a number P. 1¬beta P =. If the error beta is 0,20, then the power is 0.80. That means that the test has 80% of probabilities “of seeing” a difference of certain magnitude between two treatments and a 20% of not seeing it although exists.

The number of necessary patients (n) so that a clinical study reach sufficient to be able statistical must calculate before the study begins. The calculation of N depends on the magnitude of the difference between the treatments and the value of the error chosen alpha and beta. If a small difference between both treatments exists but it is desired to establish that difference with high statistical power, many will be required. patients, sometimes so many that the study never perhaps gets to complete itself (very expensive, very prolonged in the time). By this it is that almost all the studies of phase 111 are made in big groups of patients, are multicentric and multinational, because no isolated hospital would by itself have so many elegibles patients for a test.

The studied groups are groups of patients who represent the population like a whole that is that the criteria of inclusion and exclusion are ampler than in phase 11 (for example, subjects with more than a disease than are being dealt at the same time with other concomitant medicines). The Plan of Clinical Development includes habitually different studies from Phase III.

The relevance of the studies of this phase is in the fact that there is no evidence that indicates superiority of a treatment on another one if a comparative study has not been carried out that demonstrates it. Time concluded tests of phase III, if the new treatment were superior or has the effectiveness that assumed, is probable that is approved for the indication (pathology) in which demonstrated that he was superior to habitual o was effective. If the new treatment were inferior to the habitual treatment or had a poor therapeutic answer, is probably not approved and is necessary to evaluate if the new drug has another therapeutic possibility, with which it would become to begin the circuit of studies, or no with which its development would give in.

Phase IV

The approval of a drug for its commercialization does not mean the aim of the clinical investigation for that drug. Let us take by example the aspirin, approved in 1899. It took until the decade of the 80 to identify its properties like platelets antiaggregant. This opened another therapeutic and commercial horizon different from the original one, that it had to be studied.
In phase IV (post-approval of a drug for a certain indication), new indications of the drug and new applications are evaluated, some very novel and creative. One is to respond to all the questions that were left slopes in the previous stage. Studies are made in populations different from patients. Of additional way, studies with some other competing leader in the market or of recent approval or in specific populations not studied previously can be done (metering in old, children, patients with renal fault).

In this stage it continues studying the security of new drugs, since rare collateral effects of low incidence but dramatic, they can not be detected before the approval.

Let us remember that, in average, less than 5,000 patients they have received the new drug during phases 1, 11 and 111 (sometimes the number is much smaller). In resistance, in a single country they can be sold and be used up to 20,000 units or more of a new drug in the first month of commercialization.
The experience acquired during the clinical investigation of a new drug, often sees decreased by the enormous number of patients exposed from the commercialization, reason why it is important “to watch” what happens. Of there the expression “pharmacovigilance” that is used for the studies of phase IV which they are made in very numerous populations of patients with the intention of detecting the presence of adverse events and the different plans that are made for the detection of adverse events in patients that take a medicine determined by medical indication and not to participate in clinical studies.

If a drug were approved for its consumption in the population, but it is desired to study it in another dose, indication or pharmaceutical formulation the route of phases will begin again from phase II.
All clinical investigation, anyone is their phase, consists of following stages:

/Planning /Data collection. /Analysis of the data. / Communication .

Each one of them finalizes where the other begins, when the statistical method is used.
We can simplify the previous scheme reducing it to two great stages:

• Planning: it includes the previous activities to the beginning of a clinical study, between which we can mention the following ones:

1. Identification of the problem or hypothesis

2. Bibliographical search

3. Writing of objectives

4. Definition of the population and shows

5. Description of the scope of the study

6. Election of the type of study or design

7. Identification of the variables or characteristics to study

8. Election of the methods of data collection

9. Description of the procedures for the harvesting of the information

10. Election of the procedures for security

11. Planning of the data processing

12. Estimation of the resources

13. Design of the contingency plans

This stage finalizes with the writing of the investigation protocol .

Execution: it is the beginning of the investigation that it includes

1. Selection of the population or shows in which it will be developed investigation

2. Random allocation of the participants to the therapeutic intervention

3. Harvesting and registry of the data

4. Safety measures

5. Analysis of the data

6. Interpretation of the results

7. Writing of the scientific report

This stage concludes with the publication or presentation of the results to the scientific community and marks the aim of the investigation.
The scientific report is a document where the results and the conclusions of a study are, accompanied by a summary on the used methods and the difficulties that appeared during their execution. The scientific information of the different studies made during the development from a new product are the bases of the approval for their commercialization and comprise of “dossier” that it appears to the Regulatory Agency with this intention.

Chapter 1.2 .Introduction to clinical trials. Phase II & III studies.

2007-05-18T15:02:00.000-07:00

Phase II

If the work made with the new molecule well were planned and executed and phase I were completed finding the answer to the three fundamental questions of this phase (safe dose recommended, profile of toxicity and pharmacokinetics in human beings), it will know that dose of the new drug is going away to use in the studies of phase II.

Although in this level still it is not known if it produces some therapeutic effect in the human being. For this reason the phase II is developed, whose fundamental objective is to obtain an estimation of the therapeutic effect of a new drug and its toxicity in human beings.
The studies of phase II are made in groups of small volunteers, 100 to 200 people, who unlike the volunteers of the studies of Phase I, are not healthy but patient people who suffer the disease for which the drug has been developed. Sometimes, considering the nature of the drug, these studies can be made in healthy volunteers. For example, if it is wanted to study the effect of a diuretics can. do in a healthy volunteer, but could only be demonstrated to an effect antinflammatory in patients who have inflammatory disease.

Are studies are noncontrolled because the effects that the new drug in the group of patients produces not compare with the effects produced by placebo or another medicine known in another group of patients or group control.
In this phase one looks for to evaluate the therapeutic effect and the toxicity of the new drug. The therapeutic effect of the drug is expressed like the percentage of treated patients that reaches a certain level of answer. The normalization of clinical parameters like for example the fever disappearance is understood by answer, of laboratory like by example the negative of viral load and complementary examinations like for example the reduction of a radiological tumor. The toxicity is analyzed in descriptive terms according to the adverse or undesired events that are pronounced in the patients dealt with the new drug.

Another one of the objectives of this phase is to determine the optimal therapeutic dose and their effectiveness (relation studies dose-answer), that is the minimum dose of medication that produces the maximum effect (or the sufficient effect) without toxicity, reason why studies with different doses are made beginning by dose and the form of administration recommended after studies 'of phase I. When finalizing the studies of Phase II the dose will be known that soon will be used in the studies of phase III.
Phase II usually is subdivided in IIA (demonstration of the clinical activity or effectiveness) and IIB (clinical utility and regimes of optimal dose).

For each drug it corresponds to make at least a study of phase II in patients who suffer the disease for which she is planned to use it. This point is very important since the economic requirements of time and resources limit the evaluation only a number very reduced of pathologies or clinical situations. Therefore, the future of a drug it will be decided on the basis of the appropriate selection of pathologies in which it will be evaluated. This selection arises from the information on the mechanism of action (preclinical investigation), the tolerance doses (clinical investigation phase I) and the formulation of hypothesis on the potential utility of the drug in a determined physiopathological situation.
During this phase they are continued collecting security data, pharmacokinetics, pharmacodynamics and is determined as it will be the manufacture of the new medicine and which it will be its final pharmaceutical form.

Phase III

If the results of phase II were good, will have to be defined if the new drug is really effective and will be able to defy to the best treatment available for the disease
in study.
The studies of phase III take I finish in patients who suffer the disease in which the new drug was used without problems in phase II.

These studies are characterized for being controlled, that is that a group of patients are who receives the medication in study and another group of patients receives another medicine that in theory would have to be the best existing treatment in the market for the disease in study. The effects of both medicines in the different groups from patients are compared to each other. It can have more than 2 groups of different treatments depending on the studies. If another treatment for the disease did not exist in which it was planned to use the new drug, placebo in the group will be used control. Placebo is the copy of a medicine that does not have the active principle that characterizes it.

The allocation of the treatment that each one of the groups receives makes at random. The chance is used so that the groups are comparable, so that all the patients have the same possibility of receiving anyone of the treatments of the study and to avoid distortions in the comparison between the groups. The studies in which the allocation of treatments is made at random call randomized.

The objective of the clinical studies of phase III is to determine the effectiveness and security (or toxicity, according to it is desired to watch it) of the new drug compared with the habitual treatment for the disease in study or with placebo, throughout the time, in a group of patients.

The sensitivity and specificity of the studies of Phase III depends on several factors that are decided in the beginning of each one of the studies. Let us suppose that a study of phase III with two branches of treatment is being carried out, treatment To versus treatment B. In this comparison different levels can be tolerated from error when affirming that a medicine is better than another one or when assigning a causal relation to the medication of the study. Error is called alpha to the probability of interpreting like different the results from the treatments , and B, when in fact that difference must at random, that is that does not exist. In other words, the error alpha is the probability of having a false positive (for example it concludes that “the new treatment is better” and in fact it is not it). The value of the error alpha commonly admitted in the clinical studies is 0,05, which means that a 5% of probability exist of saying that there are differences between the treatment A and treatment B when in fact there is no it.

Chapter 1.1.Introduction to clinical trials.

2007-05-10T14:02:00.000-07:00

The animal studies, and especially toxicological, have been criticized by defending organizations of the animals. They are essential to the future establish the necessary parameters of security for use in humans. In this stage of the development of a new molecule they are made, generally, the following studies:

1) Pharmacodynamics studies: To evaluate the actions and effects of drugs in the organism through its interaction with receivers that can be more or less specific and
to establish the mechanism and place of action.

2) Pharmacokinetics studies : To evaluate the new drugs in the organism are processed, that is absorption, how they are distributed and in which it starts off are deposited (distribution), in what organs are processed and acted, like are degraded and which they become (metabolism), by where, when and in what it forms are eliminated of the organism (excretion). Once a new drug has studied in vitro and alive in animals (preclinical investigation), it can be ready to be evaluated in human beings (clinical investigation) or can determine that it will not study in human beings due to different reasons, between which, its toxicity is one of most excellent. This last situation represents that it has been I truncate the development of the new molecule. The clinical investigation is the tool fundamental to demonstrate if the new drugs are safe and effective to be used in human beings in massive form.

Within this context, each one of the clinical studies that are carried out with these drugs, will have to be planned like a block within the Clinical Development Plan (CDP). The CDP is the set of strategies; written and approved that it establishes a clinical series of studies or tests that will be the bases to sustain to the development and commercialization of a product in investigation. Each one of the clinical trials including in the CDP is a careful experiment and correctly designed and ethically justified, whose objective is to evaluate the effectiveness and security of a new drug. This definition puts emphasis in 3 fundamental aspects of the clinical studies: the necessity to respond to a concrete problem, the necessity of scientifically corrects an experimental design and you collect them ethical to take for being experiments in human beings. Results of these studies clinical, that offers information about the therapeutic value of drugs and the risk that implies its use, will be presented to the regulatory authorities, that will give the future approval for their commercialization So that a clinical study fulfills necessary the ethical requirements will be due to follow the , norms and regulatory requirements established by the Codes of Nüremberg, the Belmont Report, the declaration of Helsinki, the International Conference of Harmonization _Good Clinical Practices (ICH-GCP), the Code of Federal regulations of the Food and Drug Administration (FDA-USA), the guidelines of the European Agency of Evaluation of Medicines (EMEA), the suggestions of the Latin American Conference of Harmonization, the local recommendations of the WHO and regulations, already mentioned in the chapter on “regulatory Frame of the clinical studies”.

The process of clinical investigation is divided in four phases that serve like markers in the development of a new molecule. At the present times these phases are clearly are not delimited but they serve to frame the process. For example, a new drug that already has been evaluated for an indication and has demonstrated to be effective and safe can be being evaluated for the first time for another indication being in two phases different from its development. Phase I the studies are included in this phase in which the drugs are evaluated for the first time in human beings. These studies make specialists in pharmacology, in a number very reduced of healthy volunteers or cohort (not more than 12 or 25 people) to those who it is paid to them by his participation in the study. The term cohort (derived from the Roman military language) means homogenous group of people. The homogeneity in the clinical studies is determined by the criteria of inclusion (characteristic that they must fulfill the people so that they can participate like subjects of the investigation studies) and exclusion (those characteristics that have the people whom they love to participate in investigation studies, but that do not allow them to be selected for it). In the case of serious diseases in which the new drugs usually have important collateral effects, as is the example of drugs for the treatment of cancer or AIDS, the studies of phase I usually are carried out in patients instead of healthy volunteers.

On the one hand, it is not considered ethical to put under healthy individuals to the inherent risks of aggressive and toxic treatments, and on the other hand many of the patients already have exhausted their therapeutic options and this new molecule can be an option different from treatment. In the studies of Phase I all the members of the group of volunteers receive the same dose of the new drug. They are not comparative studies, because the groups in treatment do not compare themselves to each other. It is begun with a dose that is calculated from the animal studies. A small fraction (1 /l0 or 1/20) of the dose usually is chosen that causes serious toxicity in the most sensible species (usually, this means 1 /l 0 of DL 10 in mice). The more low it is voluntary the initial dose the more will be required in each group to evaluate the new drug. S.A. to evaluate the results of the studies is verified that the used dose is safe, is progressed in the investigation either administering to multiple doses or greater and the same dose per periods the more prolonged doses with the intention of establishing the tolerance to the new drug. The objectives of phase I are: 1) To identify the safe rank of dose of the new drug, to be used in studies of the following phases 2) To identify the maximum tolerated dose, beyond which the toxicity is limiting for its use 3) To describe the toxicity in human beings (for the first time) 4) To describe the pharmacokinetics in humans (for the first time).

There are so many questions at the time of making the studies of phase 1, that is due to be very preservative reasons why strict norms exist that regulate the form and the conditions in which they are carried out. If the drug is considered very dangerous or uncertain, the clinical tests will be suspended, which could represent that all the projects related to this new molecule are interrupted. The clinical tests of this phase can be completed in a few months if everything leaves or, or in a year or the more if there are difficulties, in the worse possible scene.

Dr. Hirose

Chapter 1.0. Introduction to clinical trials.

2007-05-07T12:04:00.000-07:00

The investigation and development of a new drug, biological product or medical device are a long and complex process that follows a logical, systematic and planned sequence in careful form and that requires the application of the scientific method, the participation of disciplinary groups and adapted economic resources. In this chapter a general vision of the process of investigation of new drugs will show to you.

The development of a novel molecule has particular characteristics that define:

1) A small fraction of discovered molecules only gets to commercialize itself (one calculates in approximate form, that of 5000 new molecules reaches the objective one of them)

2) It requires an important investment in time and money (an average of 7 to 15 years and tens to hundred of million dollars)

3) It involves manifold aspects (ethical, commercial, regulatory and legal scientists,)

4) All products that arrive at the commercialization are not useful nor persist in the market for always. Some must be retired of the market because they produce adverse reactions and others become obsolete with the passage of time.

The new molecules, candidates to be the medicines of the future, arise from very diverse situations being those that can be mentioned a rational molecular design, the synthesis in a research laboratory, the synthesis of analogs of a successful molecule already approved (derived improved from a drug leader to whom a structural modification is made to him that until can be modest and sometimes almost trivial) and advantage of an accidental finding.

Once obtained the new molecule that is promissory, one takes place in series to study its properties physical-chemistries, their stability, its solubility and other effects in systems acelullar (purified enzymatic preparations) and in human cells animals or within test tubes, in a research laboratory. This type of studies denominates “studies in vitro”.

Once known the characteristics the new molecule in vitro, it is come to study in experimentation animals. The first studies are carried out to evaluate the poisonous effects produced by the administration of very high a unique dose, is what it is known like evaluation of acute toxicity. Generally, it is chosen as animal of experimentation for this type from studies to the mice by two reasons its small size allows to obtain this effect with doses lower than those than they would have to be used with

animals which implies minors costs and is normalized procedures of written work to evaluate acute toxicity in mice, but there are no them for another type of animals.

After studying the effects of high a unique dose, it is come to administer several doses that are increased in progressive and logarithmic form to different lots from mice, to determine: 1) what dose generates the wished therapeutic effect in 50% of the laboratory animals , denominated effective dose 50 (OF 50), 2) what doses that kill to 50% of them, well-known like lethal dose 50 (DL 50). These studies are including within the training group of acute toxicity. The quotient between OF 50/DL 50 is known like therapeutic index. A drug is considered more insurance whichever greater is its therapeutic index. Because to calculate the therapeutic index the collected data of the studies of acute toxicity are used, this one index does not offer information on the possible effects of

the new molecule in the long term.

To aim to satisfy the requirements with the regulatory authorities, he is frequent that are made studies of acute toxicity in another erosive species (typically rats) and at least in a no erosive species (typically dogs), in order to obtain preliminary evidence on the different answers from the different species from the new molecule.

Once well-known the acute toxicity of the new molecule goes to the study of the sub acute toxicity. To the experimentation animals the new drug is administered to them during several days or weeks and the produced effects are evaluated.

The studies to evaluate the effects to length - term of new molecules (chronic toxicity) is always those that imply more effort of investigation because the animals must be maintained during more time, is consumed greater amount of the molecule, requires more work of technicians and specialized professionals, etc. By this reason, the studies of chronic animal toxicity are limited in the time and they do not extend beyond the 6 months being infrequent that are very made prolonged studies, although the new drug is designed for use prolonged in patients, like for example medicines for - the treatment of arterial hypertension, diabetes, hypercholesterolemia or osteoporosis. These studies are of crucial importance for the patients and the society since they allow to evaluate the possible mutagenic effects (alterations in the chromosomes or genes of the cells that gives origin to the hereditary malformations), terathogenic (physical alterations or of the development of the embryo in its phase of differentiation), carcinogenic (cancer production) and other effects that is made evident generally to the end of the prolonged use of drugs.

Dr. Hirose