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Posts tagged ‘Clinical Research Centre’

Chapter #4 Part 5: Questionnaire Development and Validation

Assalamu`alaikum and greetings to all…

Ramadhan Kareem to all Muslim out there. I realized that we always complained to any organizer not to conduct a workshop during fasting month as people were hungry, sleepy and unable to focus well. However, if we looked back to our history, Ramadhan is the month of victory and conquest, for example, the Great Battle of Badr. Today, Muslim faced different challenges and may Allah SWT give us the strength to carry out our Islam during Ramadhan and after it. During this fasting month, I am not excluded to attend a three days workshop on Questionnaire Development and Validation. Out of 42 participants only 5 of us are Muslim. Sad but true!

Acknowledgement to Prof Dr Mohd Ayub Sadiq @ Lin Naing for the core contents of above information.

Acknowledgement to Prof Dr Mohd Ayub Sadiq @ Lin Naing for the core contents of the information.

Concepts of Reliability and Validity

For a study, we need instruments (research tools) to measure several things. We must make sure they are reliable and valid as numbers from this tools will give information. The reliability and validity of questionnaire, interview and observation will be more complex.

What is Reliability?

Reliability is about consistency. When you repeat, you get a similar answer.

Example 1: If you ask your boss and he give different answer today, last month different answer and last year also different answer. Meaning that your boss is not reliable!

Example 2: Ask a boy to stand on a weighing machine 5 times and the results 60.2kg, 60.3kg, 60.1kg, 60.3kg, 60.2,kg. Meaning that the weighing machine is reliable.

Example 3: Ask 5 people with identical body weight of 60.0kg to stand on a weighing machine and the results 59.6kg, 59.8kg, 60.0kg, 60.2kg, 60.4kg. Among these 5 people there are no variation in actual body weights. But the poor measurement create variation due to errors  of the weighing machine.

In daily life, we always have 2 components of variation:

  1. Actual variation
  2. Measurement error variation

Example 4: If reliability coefficient of 0.9. Meaning that 90% from what you measure is true variation and 10% error variation. What are the sources of these errors?

  1. Questions are ambiguous = not clear
  2. Questions double-barreled = 1 question make 2 meaning
  3. Usage of jargons, medical or technical terms
  4. Different understanding /interpretation between interviewers
  5. Inadequate guideline/training for operator/interviewers. Eg. Measuring BP procedure. Make sure the respondent rest for 10 minutes, What type of chair you use? Do you take off the cloth or not?
  6. Quality of the tools. Eg. old weighing machine

Various Types of Reliability Analysis (RA)

1. Test-retest RA – Equipment, Questionnaire

  • Questionnaire you can ask people to do it 2 times. If you ask them to answer 5 times, they are going to kill
  • Example, glucose measurement.

2. Intra-interviewer RA – Interview

  • Interview 2 times

3. Intra-observer RA – Observation

  • Observe 2 times with same score.
  • Repeated test means more times, more resources

4. Split-half RA – Interview, Observation, Questionnaire

  • Remain in museum
  • Example 100 items and split into 50 items and 50 items. Administered once but you get 2 scores.
  • However, if items small in number, there is high risk of randomization fail.

5. Internal consistency RA – Interview, Observation, Questionnaire

  • More powerful since year 1960
  • Multiple split-half
  • You must design your questionnaire. Eg. DASS. Is it truly measure depression, anxiety and stress?
    • Depression – score
    • Anxiety – score
    • Stress – score

6. Inter-interviewers RA – Interview

  • 2 interviewers : 1st interviewer for 30 people, 2nd interviewer for 30 people
  • Example in daily life issue, in exams some teachers give higher or lower marks. It’s a matter of lucky and unlucky.
  • Inter-observers RA – Observation

Questionnaires = Items

There are 2 types of data:

  1. Numerical data – analysis that will be use will be different
  2. Categorical data – another set of analysis will be use

The outcome (either scores or categories) of the instruments must be RELIABLE and VALID.

1. Numerical Questionnaire (Type 1)

  • Total score = Composite score
  • Example: 10 items measure knowledge. If 1 correct 2 marks. If all correct, 20 marks.
  • Something that cannot be measure by ruler but can be measure by questionnaire – KAP, Depression, QoL, etc.
  • Questionnaire getting smaller some goes with gadget. DASS 42 items, now 21 items mixed-up.

2. Categorical Questionnaire (Type 2)

  • Dichotomous = Yes or No
  • Example: “Rose angina” – 7 questions when people answer, researcher can determine it’s from angina.
  • Algorithm which question to which question that you need to design

3. Categorical Questionnaire (Type 3)

  • Stand alone by itself and you do not come out with scores
  • Dichotomous – outcome is like this.
  • Example: Age, gender, education level (sociodemographic)

3 Statistical Methods for Reliability Analysis

  1. Intraclass correlation (ICC)
  2. Kappa (agreement measures)
  3. Internal consistency reliability (Cronbach’s alpha)

What is Validity?

Validity is about accuracy. How well an instrument measures what it supposed to measure. The triangulation of 3 C:

1. Content validity

  • The question must be valid in terms of content.
  • Example: Exam questions for a group of students. If in 1 year there are 5 parts of teaching, the 3 hours exam question set must cover that 1 year of teaching → coverage.
  • When you set the questionnaire, there must be a target group with particular standard level → relevance.
  • Assessed by qualitative approach (expert opinion).
  • Conduct a workshop.

2. Construct validity

  • Example: Body weight, Height
  • Something you can imagine but unable to see it. Eg. Depression score, KAP
  • 2 methods:
    • Construct validity by extreme groups
      • Example: Depression in scale of 0 to 10. 0 mean no depression and 10 is depression.
      • Statistical analysis: Independent t-test or chi-square test
    • Convergent and discriminant validity
      • Statistical analysis: Factor analysis

3. Criterion validity

  • 2 methods:
    • Concurrent validity
      • Example: You design a questionnaire about quality of life (QoL) among diabetic people. Scores from validated general WHO QoL with scores from your new QoL for diabetic people – is it highly correlated?
    • Predictive validity
      • Example: University entrance test with performance at the end of 4 years – it should be highly correlated.

4 Statistical Methods for Validity Analysis

  1. Independent t-test
  2. Factor analysis
  3. Simple Pearson’s correlation
  4. Sensitivity and specificity

How to Approach?

1st step: Design questionnaire

  • Self-administered
  • Self-administered with interviewer assisted
  • Interviewer assisted

§ Initial item selections – content validity.

§ Standardization: Administration, Scoring – learn from literature, experience, recommendation in discussion, experts, qualitative study

2nd step: Pretesting

  • Focus group discussion (5-7 respondents)
  • We are not interested on their answer
  • Instruction how people should answer, everything people can read and understand → comprehensibility
  • Face validity (informal)

3rd step: Piloting

  • Involve 30-50 respondents
  • Statistical methods:
    • Item level descriptive statistics
    • Item internal consistency = Cronbach Alpha RA
    • Factor analysis
  • Re-piloting after improvement

§ Drafting – “This is my questionnaire reliability and validity analysis.. various population..” FYI: It took 10 to 15 years for internationally validated and you need more comprehensive test for full recognition.

§ Don’t random sampling. Make sure whole range of people are there and set the quota. Eg. 25% Normal, 25% moderate, 25% severe, 25% highly depression.

§ Question – end with a “?” Item – statement with responses. Think about the scoring system. Each item have direction. Do you know how to use it?

How to do the statistical methods? I’m sorry I cannot share in this post as it involve hands on SPSS software.

Until we meet again.

May peace be upon you.

Chapter #4 Part 2: Good Clinical Practice (GCP)

Assalamu`alaikum and greetings to all…

When we talk about Good Clinical Practice (GCP), it is all about patient’s safety and data integrity. The Malaysian Guideline for GCP and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH GCP) are correlated. Honestly, to attend this kind of workshop is too mainstream for novice nurse like me. All the technical terminologies are focus more on the medical practitioners like Physician, Medical Officer, and Pharmacist. When I was surrounded by UD52, UD48, UD44, UD41.. I asked myself this question – What the heck am I doing here? This is not the place where I belong! Anyway, it was a good exposure and please do not ask me to attend this workshop again. So here, I am going to share my short term memories about it.

The Principles of ICH GCP

Clinical trials should be conducted in accordance with the:

  • Ethical principles that have their origin in the Declaration of Helsinki
  • Consistent with GCP
  • Applicable regulatory requirements

Before a trials is initiated:

  • Foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society.
  •  A trial should be initiated and continued only if the anticipated benefits justify the risks:
    1. Risk to individual subjects are minimised
    2. Benefits to individual subjects are enhanced
    3. Benefits to individual subjects and society are proportionate to or outweigh the risks

The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibilities of:

  • A qualified physician (Consultants, Specialists, Medical Officers, Dental Officers)
    • Principal Investigator
    • Sub-investigator
  • A qualified dentist

Each individual involved in conducting the trial should be qualified by:

  • Education
  • Training
  • Experience to perform his/her respective tasks

Institutional Review Board/Independent Ethics Committee (IRB/IEC) ≠ Regulatory authorities (eg. NPCB)

In Malaysia, IRB/IEC is known as MREC (Medical Research and Ethics Committee). The composition:

  • At least 5 members
  • At least 1 member whose primary area of interest is in a nonscientific area
  • At least 1 member who is independent of the institutional/trial site


  • Obtain and review study documents:
    • Study protocol
      • General information of trial
      • Background information
      • Trial objectives and purpose
      • Trial design
      • Selection and withdrawal of subjects
      • Treatment of subjects
      • Assessment of efficacy
      • Assessment of safety
      • Statistic
      • Direct access to source data/documents
      • Quality control and quality assurance
      • Ethics
      • Data handling and record keeping
      • Financing and insurance
      • Publication policy
      • Supplements
    • Informed consent form
    • Subject recruitment procedures
    • Written information to subjects
    • Investigator’s Brochure (IB)
      • A compilation of the clinical and nonclinical data on the IP that are relevant to the study of the products in human subjects
      • Concise, simple, objective, balanced and nonpromotional
      • Provides information to understand IP, rationale for administrative of IP, safety measures, insight to support clinical management of subjects, unbiased risk-benefit assessment
    • Payment and compensation to subjects
    • Investigator’s CV
  • Verify qualifications of investigator
  • Conduct continuing review of on-going trials
  • Review amount and method of payments to subjects
  • Retain all records for at least 3 years after completion of trial

Investigator The investigator should be qualified by:

  • Education
  • Approved training in GCP
  • Experience to assume responsibility for the proper conduct of the trial

Informed consent of trial subject and Patient Information Sheet (PIS) should include 20+1 explanations of:

  • Trial involves research
  • Purpose of the trial
  • Probability for random assignment to treatment
  • Trial procedure to be followed, including invasive procedures
  • Subject’s responsibilities
  • Experimental aspects of the trial
  • Description of foreseeable risks or discomforts
  • Expected benefits
  • Alternative procedure/treatment available
  • Subject compensation
  • Anticipated prorated payment
  • Anticipated expenses
  • Subject’s participation in the trial is voluntary – subject may withdraw at any time
  • Direct access to subject’s original medical records
  • Records identifying the subject will be kept confidential
  • Will be update if new information becomes available
  • Person(s) to contact for further information and in the event of trial-related injury
  • Circumstances for trial termination
  • Duration of participation in trial
  • Number of subjects involved in the trial
  • The source of the investigational product (IP) that may be culturally unacceptable

Safety reporting

  • All 6 serious adverse event (SAE) detected or being notified should be reported immediately (within 24 hours) to the sponsor:
    1. Result in death
    2. Is life-threatening
    3. Requires inpatient hospitalization or prolongation of existing hospitalization
    4. Results in persistent or significant disability/incapacity
    5. Is a congenital anomaly/birth defect
    6. Other important medical events based on medical and scientific judgment
  • Sudden unexpected serious adverse reaction (SUSAR) that is fatal/life threatening – initial report must be not later than 7 calender days, followed by a complete report within 8 additional calender days (sponsor → NPCB)
    1. Report Number and indication Initial report or Follow up
    2. NMRR ID and protocol title
    3. Principal investigator name and designation
    4. Subject ID
    5. Study site/institutional name/country
    6. Adverse Event type, description of event, action taken and outcome
    7. Name of suspect medicinal product
    8. IP Causality
  • All other SUSAR and local SAE, written report no later than 15 calender days from awareness of event by investigator

Respect for trial subject:

  • Protect subject’s confidentiality and privacy
  • Provide opportunity to withdraw early, without penalty
  • Subject’s well being monitored
  • Inform subject of new information, and to re-consent if necessary
  • Inform subject the study results, in recognition of his/her contribution to research
  • Compensate subject for research injury

Responsible for IP accountability:

  • The investigator can assign the responsibility to pharmacist or appropriate person under supervision of IP
  • Maintain record of IP
  • Stored IP as specified by spnsor
  • Explain correct use of IP to subjects

Premature termination of a trial:

  • Promptly inform subjects or institution (if necessary)
  • Written explanation to MREC, sponsor, NPCB (usually sponsor)

Trial design:

  • Stopping rules
  • IP accountability procedures
  • Identification of source data

Sponsor  Sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator:

  • Against claims arising from the trial
  • Except for claims that arise from malpractice and/or negligence
  • Address the cost of treatment of trial subjects in the event of trial-related injuries
  • Financial aspects should be documented in an agreement

The sponsor should not supply an investigator with the IP:

  • Until the sponsor obtain all required documentation from MREC and NPCB
  • Until all importation of clinical trial drugs go through customs even though a clinical trial import licence (CTIL) has been obtained.

CTIL and CTX Application

  • Categories of product:
    • Unregistered products when used or assembled (formulated or packaged) in a way different from the approved form for the purpose of clinical trial
    • A traditional product with a marketing authorisation with indication for “traditionally used” when used for unapproved indication/therapeutic claims for clinical trial purpose
  • Pharmacist required? Licence A for poisons/drugs (where applicable)
  • NMRR registration number
  • Approval from DCA, IEC/IRB


  • “The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, SOPs, GCP and the applicable regulatory requirements.” ICH GCP 1.38


  • “A systematic and independent examination of trial-related activities and documents to determine whether the evaluated trial-related activities were recorded, analyzed and accurately reported, according to the protocol, sponsor’s SOPs, GCP and the applicable regulatory requirements.” ICH GCP 1.6


  • “The act by regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor’s and/or Contract Research Organization’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority(ies).”

By the end of the workshop, we have to sit for certification examination. The exam consist of 40 Multiple Choice Questions (MCQs) but we have to choose the best answer within 1 hour.

Best of luck!


It’s all about patient’s safety and data integrity.

“Sesungguhnya di sisi Allah ilmu tentang hari kiamat; dan Dia yang menurukan hujan dan yang mengetahui apa yang ada di dalam rahim. Dan tiada seorang pun yang dapat mengetahui (dengan pasti) apa yang akan dikerjakan esok. Dan tidak ada seorang pun yang dapat mengetahui bumi mana dia akan mati. Sesungguhnya, Allah Maha Mengetahui, lagi amat meliputi pengetahuan-Nya.”

(Surah Luqman 31: 34)

Until we meet again.

May peace be upon you.

Chapter #4 Part 1: Protocol Development

Assalamu`alaikum and greetings to all…

What do you expect from a degree holder nurse? At this moment, my answer would be patient’s care giver, educator, researcher and the list will be continued along with our years of experience in the nursing field. There are differences between protocol and proposal.

In protocol development, some of the questions that we have to answer are:

  • What is your study all about?
  • What you already know?
  • What we do not know?
  • Objectives of the study – keep it clear + specific + measurable + publishable
  • Method
  • How are you going to collect the data?
  • Expected results

In Clinical Research Centre (CRC), we will learn how to do Investigator Initiated Research (IIR) and Industrial Sponsored Research (ISR). In IIR, we have one Principal Investigator – yours truly.

  • Go to National Medical Research Register (NMRR) website and create a new account.
  • Submit your protocol under Investigator Initiated Research and follow the instruction.
  • Wait for approval from Medical Research and Ethics Committee (MREC)

Documents that need to be uploaded:

  • Cover letter to National Institute of Health (NIH)
  • Patient Information Sheet (PIS)
  • Informed Consent Form (ICF)
  • Curriculum Vitae (CV)
  • Protocol
  • Case Record Forms (CRFs) aka Questionnaires
  • IA-HOD-IA form
  • Good Clinical Practice (GCP) certificate

Remember, don’t be too ambitious!

Backward Translation + Forward Translation = Validation

Dan janganlah kamu berjalan di muka bumi ini dengan sombong, kerana sesungguhnya kamu sekali-kali tidak dapat menembusi bumi dan sekali-kali kamu tidak akan sampai setinggi gunung.

(Surah Al-Isra’ 17: 37)

Until we meet again.

May peace be upon you.

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