Frequently Asked Questions (FAQ's)
Written by Hiroyuki Fukase, M.D., Ph.D.
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2. Subjects who deviate from standard reference ranges
3. History of allergic response as an exclusion criterion
4. Excretion
5. Self-answer questionnaire
6. Urinary sediments
7. Volunteer allocation
8. Cardiac Arrhythmia
9. Body temperature
10. Urine qualitative analysis
11. Changes in blood pressure and pulse rate
12. BMI (selection criteria)
13. Definition of Caucasian subjects
14. Selection criteria (Blood pressure) for elderly subjects
15. Blood sampling volumes in elderly subjects
16. Trends in data observed between screening values and post hospitalization values
17. Differences between measured and reported prothrombin times
18. IRB/SOP (memberfs definition)
1. Typefacing
Q:
Is it possible for T1/2 to signify a half-life period (pharmacokinetics parameter) instead of t1/2?A:
No. T1/2 must be used when illustrating a half-life period. T, upper case, cannot be used for this purpose as the Japanese quantitative notation method, based on the International System of Units, states that t (lower case) is used to represent time and T (upper case) is used to represent temperature. There are many other detailed rules for typefaces, which include:
-Symbols for quantities are illustrated in italics.
-Symbols illustrating superscripts and subscripts must be italic if they represent quantities (e.g. p: pressure), and Roman letters if they represent something other than quantity.
-Symbols for units are represented by Roman characters.Cmax and tmax should therefore, be shown as Cmax and tmax respectively in accordance with the notation rules of the International System of Units.
2. Subjects who deviate from standard reference ranges
Q:
How can subjects who deviate from standard reference ranges in screening examinations be included for study participation?A:
Abnormalities cannot be determined by deviations from standard reference ranges. Reference ranges are described as normal values, and the range is defined to include approximately 95% of the values in healthy people (double-range of [mean ± SD]). Therefore, 5% of healthy people may present values outside of the standard reference ranges. (Also, it should not be assumed that subjects with no deviations from standard reference ranges are always healthy).
If there are n individual items for measurement, the probability of all values falling within the normal ranges is 0.95n. Therefore, should a subject undergo 20 examinations, the probability that all values are within the standard reference ranges is less than 0.4.
3. History of allergic response as an exclusion criterion
Q:
Should volunteers with a medical history of an allergic response be excluded from trial participation?A:
We do not believe that it is necessary to exclude all volunteers with a history of moderate allergic response. According to a health survey of children in 1992-1994*, approximately 40% of students were diagnosed as having suffered from some form of previous allergy and 66% were believed to have suffered from hay fever. A subsequent investigation conducted by Chiba University School of Medicine indicated that 37.8% of 11 years olds and 64.7% of 15 year olds, had experienced a reaction associated with mites. Based on these findings, should all volunteers with any history of allergy be excluded from the target population (20-30 year-old healthy Japanese males) regardless of the nature and severity of the allergy, the remaining volunteers would not be representative of the target population. Indeed, it would be almost impossible to recruit a sufficient number of volunteers to conduct regular trials.
Moreover, there is no evidence to suggest that there is a correlation between the frequency of onset and severity of a drug allergy and the presence or absence of mild allergies (such as, allergic rhinitis or allergic conjunctivitis) in healthy people. The presence or absence of a mild history of allergies does not appear to have an influence on pharmacokinetics results.
*A health survey targeting 26,545 children at 55 schools (elementary, middle and high schools) across 13 prefectures, conducted by the Japanese Society of School Health, under the authority of the Ministry of Education.Case examples:
Volunteer No. XX:
Asthma, not associated with a drug allergy / No history of induction or aggravation of symptoms by drugs.Volunteer No. XX:
Hives, not associated with a drug allergy / No history of induction or aggravation of symptoms by drugsVolunteer No. XX:
Allergic rhinitis, not associated with a drug allergy / No history of induction or aggravation of symptoms by drugs
Most antigens associated with allergic rhinitis in Japan are thought to be caused by either house dust or pollen, although this finding has yet to be confirmed.Volunteer No. XX:
Allergic conjunctivitis, not associated with a drug allergy / No history of induction or aggravation of symptoms by drugs
70% of the antigens that cause allergic conjunctivitis in Japan, are thought to be from either house dust or pollen.All the above mentioned cases are non-pharmaceutical related events, and therefore the volunteers were judged to be suitable for admission to the Kagoshima Volunteers Association.
4. Excretion
Q:
Is it possible to request that volunteers defecate before administration?A:
We do not believe that it is possible to request people to eliminate body waste on demand, for example, prior to administration. The reason for this is that it is highly difficult to control defecation at will. Obviously, there would be many deviations should a protocol specify obligatory defecation at specific time points. A request to encourage defecation at certain time points may be included in the study protocol but realization is not always possible.
5. Self-answer questionnaires
Q:
Why are self-answer questionnaires not used for Phase I clinical trials?A:
We do not believe that self-answer questionnaires should be used for Phase I clinical trials. The rational for this is explained in the following transcript of a presentation given by our company president, Dr. Ryoichi Nagata, M.D., Ph.D. at the Japan Pharmaceuticals Manufacturers Association in November 1997:[Adverse events observed in Phase I clinical trial]
- <1>
Most adverse events are not straightforward and can be observed in healthy people who have not received drug administration or have received placebo. Therefore, large numbers of volunteers are required in order to separate adverse drug reactions from other adverse events. Although there are some exceptions, it is extremely difficult to identify adverse drug reactions in Phase I clinical trials.- <2>
According to pharmacological and toxicological distinctions, Adverse Drug Reactions (ADR) are divided into two types: predictable (Type A) and non- predictable (Type B). The method of detection depends on predictability.- <3>
There are four methods of detection detailed as follows:
- 1.
Voluntary reporting from volunteers: Targeting all adverse events- 2.
Self-answer questionnaires that target predictable events. Such questionnaires have limitations and increase sensitivity for the target item but specificity is decreased.- 3.
Questionnaires completed by others (doctor, nurse, etc.) that target predictable events. Such questionnaires have limitations and increase sensitivity for the target item but specificity is decreased.- 4.
- Simple and standardized questions. Involves the use of questions that are not leading. (i.e. Have you noticed anything out of the ordinary?)
** A Phase I trial will incorporate a method that does not limit any items, (1 or 4). The reason for this is that adverse events which are not included in the questionnaire may be overlooked. Indeed, it is very difficult to prepare a set of items specific to a test drug due to a lack of information on Type A (predictable) adverse events at the time of a Phase I trial.
The psychosomatic symptom questionnaire for use in a trial would be 3-2, and much care must be taken when interpreting the data due to the following:
-This type of questionnaire often produces a high level of false-positive responses
-Adverse events other than those raised as the items on the questionnaire can be overlooked as it is so difficult to form a set of items specific to the test drug. As a result, the sensitivity of detection of adverse events other than those on the questionnaire is reduced.
-Writing errors should be expected when volunteers complete the forms in person.
It is for these reasons that we believe this method should be avoided in the conduct of Phase I clinical trials. If we were asked to adopt such a method, we would request permission from the Sponsor that the final decision should lie with the medical investigator on completion of all examinations. Therefore, the psychosomatic symptom questionnaire would be used for reference only and test-positive items would not lead to snap judgements. In other words, the following symptoms would not be treated as adverse events:
-Those events which the volunteer has experienced prior to administration or has repeatedly experienced during the course of his daily life prior to administration and where there is no difference in severity before and after administration.
-Events which medical examinations could not confirm. (error in writing)
6.Urinary Sediments
Q:
Explain about the sediments in urinalysis?
A:
Urate, phosphate and oxalate are clinically significant only when they appear in large quantities and are associated with lithiasis. A positive observation of only one item is not clinically significant.
7. Volunteer allocation
Q:
It is said that randomly allocating subjects to each step is difficultcA:
In single-administration studies, when moving to a new step after confirming safety in the previous step, randomized allocation of active and control drugs is conducted at each step. It is very difficult to allocate subjects to each step, due to the following:
<1>
It is physically impossible to randomly allocate eligible volunteers at each step after conducting screening examinations on all volunteers during a common screening period. The screening period of the first step and that of the next step may partly overlap, even though the latter part of the steps do not overlap at all.
<2>
Volunteers generally select the step they would like to participate in according to their schedule.
8. Cardiac Arrhythmia
Q:
If an arrhythmia is observed from holter monitor examination, is it possible for the volunteer to be included in a trial?A:
Arrhythmias are often observed in healthy volunteers from holter monitor examinations. In these cases, volunteers will be admitted to a trial if similar arrhythmias are frequently observed in healthy volunteers and no other symptoms indicating the presence of cardiac disease are observed.
9. Body Temperature
Q:
What is the upper standard range body temperatureA:
Upper body temperature limit is 37.5 and is based on the following:
l The average axillary temperature of 1,094 healthy adults was found to be 36.89 and the SD was 0.34
l Mean 2SD =37.57 = approximately 37.5
10. Urine qualitative analysis
Q:
The appearance of occult blood was reported as an adverse event although measurement was not specified in the urine quantitative analysis section of the study protocol?A:
With regards to this study, Protein, Glucose and Urobilinogen were the parameters defined for analysis in the study protocol. However, the qualitative instrument used for urinalysis in our clinic automatically checks for occult blood and displays all results. Therefore, the abnormal reading of +2 observed in Subject No. XX was observed by the investigator and therefore reported as an adverse event. No other positive finding was noted for any other subject in this particular trial.
11. Vital Sign Assessment
Q:
Please explain the criteria for evaluating blood pressure and pulse rate?A:
Based on the reference texts referred to below, changes in blood pressure and pulse rate are tabulated if they are outside the following reference ranges:
Systolic blood pressure: ±20mmHg
Diastolic blood pressure: ±15mmHg
Pulse rate: ±20%
These parameters are based on the normal physiological changes that occur within a 24 hour period in healthy people and are considered as average or mean natural deviations.
However, it is not correct to assume that measurements taken immediately before administration are baseline values and it is very difficult to state categorically that the values observed are indeed deviations from the referenced ranges.References:
- 1. C. Lentner, Heart and Circulation, Geigy Scientific Tables 5, 10, CIBA-GEIGY Limited, Basel, 1990
- 2. C.Lentner, Heart and Circulation, Geigy Scientific Tables 5, 26, CIBA-GEIGY Limited, Basel, 1990
12. Body Mass Index, BMI (selection criteria)
Q:
Is it possible to include a volunteer with a BMI value between 19.8 and 24.2?A:
Most volunteers in Phase I trials in our clinic are in their twenties. According to the national nutrition survey in 1997, the average BMI of 20-29 year-old males was lower than previous generations by 0.9-1.2.
If we use the above criteria for BMI distribution and our target population is over twenty years, we will be limited to 49.7% of the population. The BMI of this generation of 20-year-olds is lower than that of previous generations and if we only target 20-year olds then the number of volunteers eligible for participation will be reduced even further.
If we were to use a BMI range ±20% then we would eliminate over half the 20 year old age group population and recruitment would be extremely difficult. Moreover, it would be difficult to transpose trial data as the results would be somewhat biased towards the target population.
With reference to the above, if we use the twenty year old average BMI ±1 standard deviation, (which will include approx. 70% of the target population), then we would request the BMI measurement values to be 19-25.6.
13. Definition of Caucasian subjects
Q:
Please explain the rationale for defining subjects as Caucasian?A:
Race is a concept that classifies mankind according to characteristics such as skin and eye color, hair characteristics, and physical attributes such as physique. However there is no method for defining Caucasians on the basis of a listing of physical characteristics (light colored or brown skin, wavy or curly hair, generally narrow nose etc.).
Furthermore it is difficult in itself to list common characteristics of Caucasians, as it is said that within a Caucasian population, many different systems may be found.
Moreover when considering the generally used race classification system (Black, Caucasian, Asian and etc.), it is thought there to be little meaning in enumerating the physical characteristics of a volunteer to confirm which race they belong to and whether they meet protocol specifications. Therefore it is not possible to define race in this way.
Due to reasons mentioned above, the clinical studies we have conducted in Caucasian subjects, we have adopted a more realistic definition of having both parents being similarly Caucasians. Therefore we propose a practical definition of Caucasian by asking volunteers whether both of their parents are similarly Caucasians.
14. Selection criteria (blood pressure) for elderly subjects
Q:
Please explain the rationale concerning selection criteria (blood pressure) for elderly subjects@
A:
In the 1999 the National Nutritional Survey (distribution of minimal and maximal blood pressure by sex and age), the following results were reported:
Males aged 60-69 years with systolic blood pressure greater than 140mmHg, 52.9%, Males aged above 70 years with systolic blood pressure greater than 140mmHg, 59.4%,
Females aged 60-69 years with systolic blood pressure greater than 140mmHg, 47.3, Females aged more than 70 years with systolic blood pressure greater than 140mmHg, 58.1%.
From these results for elderly subjects, aged above 65 years, it is clear that the selection criteria to be set in the reference range, as systolic blood pressure below 140mmHg. If this is the case then, more than half the population will be unsuitable for selection and subject recruitment will be extremely problematic.
Moreover the blood pressure values of those subjects selected would comprise a gspecialh group, which is not representative of the countryfs elderly population and the results may therefore be doubtful.
The report referenced above gave the following additional statistics:
Males aged 60-69 years with systolic blood pressure greater than 160mmHg, 17.6, Males aged above 70 years with systolic blood pressure greater than 160mmHg, 18.8%, Females aged 60-69 years with systolic blood pressure greater than 160mmHg, 12.2, Females aged more than 70 years with systolic blood pressure greater than 140mmHg, 16.8%.
Therefore should the selection criteria set the reference range as systolic blood pressure below 160mmHg; it is possible to judge that recruitment of subjects that are representative of the countryfs population is possible.
