Lab07 - Studies to verify therapeutic safety

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Introduction

The therapeutic safety is pursued throughout the development of a new therapy in the preclinical and clinical phases.

The study taken as an example was published in 2017 in the open-access journal Anemia by Melvin H. Seid from Unified Women’s Clinical Research, Winston-Salem, USA; Angelia D. Butcher from Luitpold Pharmaceuticals, Inc., Norrisville, USA, and Ashwin Chatwani from Department of Obstetrics and Gynecology, Temple University School of Medicine, Philadelphia, USA under the title „Ferric Carboxymaltose as Treatment in Women with Iron-Deficiency Anemia”. It is a study that looks at the safety of a way to administer a therapy in the clinical phase after launching the drug on the market.

The article is available and can be accessed at: https://www.hindawi.com/journals/anemia/2017/9642027/

This trial is recorded in ClinicalTrials.gov, NCT00548860:

https://clinicaltrials.gov/ct2/show/NCT00548860?rslt=With&cond=%22Anemia%2C+Iron-Deficiency%22&draw=3&rank=27

Definitions used in the study

Iron deficiency anemia (IDA) - is a condition in which there is a deficiency of healthy red blood cells. In this study, IDA is considered to be present if hemoglobin (Hb) ≤ 11.0 g / dL. For postpartum (Hb) patients, it was obtained at least 18 hours after birth.

Severe menstrual bleeding was defined in this study as "≥1 of the following in the past 6 months: (a) Inability to control flow only with tampons; (b) use of> 12tampons per period or 4 tampons per day; c) the presence of clots; or (d) the duration of the period> 7 days.

Standard Medical Assistance (SMC) - "Doctor-directed or non-prescription medical treatment".

Cardiac risk: Subjects with 1 or no cardiac risk factors were designated as having low cardiac risk. Subjects with 2 or more cardiac risk factors including smoking, high blood pressure, cholesterol in the blood, diabetes, overweight or obesity, physical inactivity and family history of heart disease (father / brother before the age of 55 or mother / years) were designated as having increased cardiac risk.

The weight of the postpartum patient was defined as the pre-birth weight.

Study Scenario

Based on the study presented above, a similar, simplified study was carried out in the following.

The objective of the multicentre, randomized controlled trial (RCT) was to evaluate the safety of the maximum dose of 15 mg / kg (maximum 1000 mg) of Ferric Carboxymaltose (FCM) compared to standard medical care (SMC) for the treatment of iron deficiency anemia (IDA) in women with postpartum IDA (after birth) or in women with severe menstrual bleeding." The endpoint was the occurrence of a serious adverse/side effect.

 130 centers attended this study. Contact with patients was done through "a screening visit and two study visits on day 0 and day 30". The study had the approvals of the ethics committees of the respective centers, the patients signed their informed consent. The study was conducted "in accordance with the guidelines of good clinical practice and the Helsinki Declaration"

 This study included women who:

  • were in postpartum and presented IDA
  • have strong menstrual bleeding and IDA

Exclusion criteria. Women who had:

  • a history of anemia, other than IDA, due to pregnancy / birth or heavy bleeding during menstruation;
  • current treatment with myelosuppressive therapy or asthma therapy
  • a history of hypersensitivity to FCM
  • planned surgery
  • an active infection including hepatitis B or C.

 "Subjects were randomized in a 1: 1 ratio using a central voice response interactive system to receive either IV FCM or SMC. Randomization was stratified by:

  • • IDA etiology (postpartum or severe menstrual bleeding)
  • • initial hemoglobin values ​​≤ 8.0, 8.1 to 9.5 or> 9.5 g / dl.”

Subjects in the FCM group received FCM in a slow intravenous infusion over 15 minutes on day 0. Subjects from the SMC group were treated according to SMC from day 0 to day 30.  

The therapeutic safety was assessed by physical examination and blood samples taken on day 0 and day 30. Patients were asked and encouraged to report adverse effects.

"The sample size of 750 subjects per group provided a power of about 80% to detect a statistically significant difference in the incidence of serious adverse events when the incidence was 5.25% for FCM and 2.5% for SMC." Lost subjects from the study were removed from the analysis.

Statistical analysis.

 The variables were described using average, the standard deviation, the median and the interquartile interval. Differences between treatment groups were analyzed with the Chi square test. The level of significance alpha was chosen to be 0.05.

Research protocol

Aim

The aim of this study was to evaluate the safety of the maximum dose of 15 mg / kg (maximum 1000 mg) of FCM for the treatment of IDA.

Objectives

  • Studying the existence of adverse effect / effects:

 The study will answer the question:

Are there any differences in the frequency of serious adverse reactions according to treatment?

  • Studying the size of the adverse effect/effects (quantification of importance): By calculating the individual risk indicators of those exposed (RIE), individual risk of non-exposed (RIN), relative risk (RR), risk difference (RAR), the number needed to cause physical injury (NNVF)

Domain of research

The research domain of this study was the evaluation of a therapeutic approach.

Study type

Based on study objectives : analytical

Based on the results: experimental study

The type of the study based on it`s design: cohort, trial with parallel groups.

The type of study based on the development phase of a drug was Phase IV (clinical).

Validity of the study

Subjects were assigned to the treatments in a randomized manner. Allocation was not masked "allocation concealed". The analysis was of the "safety analysis set" type. The study was open (open label). The trial was controlled.

The way the results are analyzed may differ. In the case of analysis of the results of a therapeutic safety study, it follows the principle as it was treated ("As-Treated Principle"). There are the following methods for including subjects in the analysis: analysis set (all patients who took the treatment at least once during the study), how much time it was followed (“Time-followed" - all patients who have been tracked for a specific time) and the group in which they were treated ("Treatment Group" - those who took the treatment).

Target population and study sample

Target population

This study has as target population women (as a demographic feature) with the following clinical features: postpartum IDA patients or patients with severe menstrual bleeding.

Accessible population

The samples were selected from 130 locations in the US, which are not specified either as a name, neither as a type nor as a location.

Study sample

Inclusion criteria

Women (as a demographic feature) were selcted with the following clinical features: postpartum IDA patients or patients with severe menstrual bleeding.

Exclusion criteria

The exclusion criteria can be grouped in this study as::

  • Biassing factors: recent gastrointestinal bleeding (≤ 3 months); significant acute blood loss (other than at birth); a history of anemia, other than IDA, due to heavy pregnancy / birth or severe menstrual bleeding; current treatment with myelosuppressive therapy or asthma therapy; recent (≤ 1 month) transfusion of blood, iron IV, erythropoietin or other experimental drug administration; recently pregnancy lost; planned surgery; an active infection including hepatitis B or C; known human immunodeficiency seropositive virus (HIV); a malignant disorder; hemochromatosis; significant cardiovascular disease; increased liver enzymes; drug use; on day 0 levels of Hb in the care point> 12.0 g / dl; on day 0, a systolic blood pressure (TAS)> 160 or 100 or 40 mm Hg.
  • Adverse effects: history of hypersensitivity to FCM .

Sample size

The authors mention in the article the impact of waist on the validity of the study results. We believe that the size of the samples was sufficient. The incidence of adverse effects was 5.25% for FCM and 2.5% for SMC. The beta error was 20%, the power of the test strength was 80%.

1.1.1         Data collection method

Based on the studied population: sampling. The type of sampling method is not mentioned.

Based on the duration of data collection: longitudinal, prospective.      

Based on the grouping method: in this study was a sample (cohort) initialy selected initialy from the population, as two divided groups according to treatment in the administration phase/analysis after randomization (the stydy was open).

1.1.2         Statistical analysis.

The variable involved in the treatment safety study was a qualitative variable, dichotomial type.

Expected results. Data analysis and presentation

The study was conducted on a sample of 2000 women. 1000 women were randomly chosen to be treated with FCM,  the remaining 1,000 women benefiting only from SMC. The simulated data and statistical processing are found in the B_IDA.xlsx file on the discipline website.

 Assessing the comparability of the studied samples:

We need to answer the questions:

  • Is there a statistically significant difference between Hb averages on day 0 in patients who were subsequently treated with FCM over those who subsequently received SMC treatment?
  • Is there a statistically significant difference between the frequency of IDA causes in patients who were subsequently treated with FCM over those who subsequently received SMC treatment?

Results: Table I presents the initial characteristics of the two intervention groups.

Table I. Initial situation of patients with IDA followed by the two intervention groups

Characteristics of subjects

FCM

(n=1000)

SMC

(n=1000)

p

Test

Hb day 0 (mg/dl)

9,73±1,23

9,64±1,21

0,181

Student Test for equal variations

Nr. Postpartum women n (%)

627 (62,7)

627 (62,7)

1,000

CHi-square

Values ​​are represented as arithmetic mean ± standard deviation for data following a normal distribution or number of subjects (percent);n – number of subjects; FCM - Ferric Carboxymaltose; SMC – standard medical assistance; Hb - hemoglobin.

Study of the relationship between serious adverse effects and treatment with FCM

In the following, we answer the question:

Are there any differences in the frequency of serious adverse reactions according to treatment?

 Results: Table II shows the frequency of serious adverse effects in patients who received treatment with FCM versus the frequency of serious adverse effects in patients who received SMC treatment.

Table II. Serious adverse effects in the two groups

No serious side effects

With serious side effects

Total

Treatment with FCM

994

6

1000

Treatment with SMC

978

22

1000

Total

1972

28

2000

FCM - Ferric Carboxymaltose; SMC – standard medical care.

The result of the statistical test was p = 0.002 (CHi-square test).

 Quantifying the serious adverse effects:

Indicators: ratio of the experimental event (REE) was 0,006, ratio of the control event (RCE) was 0,022, relativ risk (RR) was 0,27, absolute risk reduction (ARR) was 0,016, number needed to treat (NNT) was 63.

Interpretation of results. Discussions

Interpretation of results from statistical point of view

Studying the comparability of the samples at baseline   

Question: Is there a statistically significant difference between Hb averages on day 0 in patients who subsequently received FCM treatment over those who subsequently received SMC treatment?

  • Answer: Because p> 0.05, we can not say that there is statistically significant difference between Hb averages at day 0 in patients who subsequently received FCM treatment over those who subsequently received SMC treatment (9.73 ± 1.23 vs. 9.64 ± 1.21, p = 1.181).

The difference in Hb averages between the two groups was 0.09 ml / dL.

Question: Is there a statistically significant difference between the IDA cause in patients who were subsequently treated with FCM over those who subsequently received SMC treatment?

  • Answer: Because p> 0.05, we can not say that there is statistically significant difference between the IDA cause in patients who subsequently received FCM treatment over those who subsequently received SMC treatment (62.7% vs. 62.7% p = 1,000).

The difference between the percentage of postpartum women in the two groups was 0%.

Conclusion: Samples are comparable before the study.

Studying the existence of the relationship between the frequency of serious adverse effects and treatment with FCM

Question: Are there differences in the frequency of serious adverse reactions according to treatment?

  • Answer: Because p 0.05, the frequency of serious adverse events is influenced by the difference in treatment (FCM vs SMC). Patients treated with FCM had statistically significantly fewer serious adverse events than SMC treated patients (0.6% vs. 2.2%, p = 0.002). These results relate to what happens in the target population.

The percentage difference between the two groups of serious adverse event frequencies was 1.6%.

Studying the frequency of the adverse effect/effects (quantification of importance)

Below we have exemplified the interpretation of the therapeutic safety quantification indicators:

REE=0,006 interpretation: 0.6% of patients who received treatment with FCM had serious adverse effects

RCE=0,022 interpretation: 2.2% of patients who received SMC treatment had serious adverse effects

RR=0,27 interpretation: because RR 1 we can say that treatment with FCM had a protective effect against the occurrence of serious adverse effects compared to SMC treatment.

Comment: We can calculate the risk of serious side effects if the patients followed SMC compared to FCM, then RR = 0.022 / 0.006 = 3.67. In this case, the interpretation is: the risk of having serious side effects if the patients followed the SMC was 3.67 times higher than if the patients followed the FCM.

  • ARR=0,016 interpretation: there were with 1.6% fewer serious adverse events in patients who received FCM than those who received SMC.
  • NNT=63 interpretation: in the treatment of 63 people one has serious adverse effects in addition to treatment with SMC versus FCM treatment

Indicators (punctual estimators) refers to what was obtained on study data.

 

                Safety of therapy from a clinical point of view

                FCM experimental therapy was well tolerated and clinically presenting risks were comparable to SMC and even fewer. Any treatment that brings a difference in the occurrence of major adverse effects (1.6% less in our case) can be considered clinically important.

Conclusions of the study

"In conclusion, this study demonstrated that a single dose of FCM of up to 1000 mg administered by IV infusion is safe in the treatment of IDA in postpartum women and in women with severe menstrual bleeding."

To remember

How do we recognize a therapeutic safety study?

  • the analysis is exposed-unexposed
  • are experimental studies, the effect of an intervention is studied
  • side effects are studied.

LAB 08 - Practical Activity

Data file - EXCEL

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