The material was supported by an educational grant from Ferring HOW TO DESIGN A STUDY Nikolaos P....

The material was supported by an educational grant from Ferring

HOW TO DESIGN A STUDY

Nikolaos P. Polyzos M.D. PhD

Type of Study and Level of Evidence

RCTs

Meta-analyses

of RCTs

Cohorts, casecontrol studies, cross-

sectional surveys

Case series, case reports, guidelines, expert opinions

LEVEL I

LEVEL II

LEVEL III

What type of study should I perform?

It depends on what you are seeking

General Types of Studies

• Observational:– Searching for association or relationship

• Interventional: (clinical trials)– Validating a specific treatment protocol

Observational Studies

• Cross-sectional studies• Case-control studies• Cohort studies

Cross-sectional study

Cross-sectional surveys

A “photograph” of the population at a specific moment

Aim• Assess the prevalence of acute or chronic

conditions• Check association between characteristics of the

population

Example of cross-sectional study

Association of blood type and patient characteristics with ovarian reserve.• Determination of blood type• Determination of FSH levels

Timberlake KS et al., Fertil Steril. 2013 

Case-control study

Case-control studies (1)

Cases (patients with a disease)

Controls (patients without the disease)

Advantages:• Case-control studies are simple to organise• Retrospectively compare two groups• Aim to identify predictors of an outcome

Case control studies (2)

CASES (present)

CONTROLS (absent)

(?)

(?)

Exposure

Investig

ator

Disease

e.g. Endometriosis

e.g. BMI

Retrospective cohort

Deep infiltrating endometriosis is associated with markedly lower body mass index: a 476 case-control study.• Cases- endometriosis• Controls- no endometriosis• Check for difference in BMI

Cohort study

Cohort studies

• Follow a specific cohort • A cohort is a group of people who share a

common characteristic or experience within a defined period

Advantage:

Can examine causal relationship and predictive ability of a marker

Cohort studies- retrospective

(?)

(?)

YES

NO

Exposure

Investig

ator

Disease-outcome

e.g.Pregnancy outcome

e.g. AMH values

Retrospective cohort

Examples of a retrospective cohort

Predictors of ovarian response in women treated with corifollitropin alfa for IVF/ICSI. Polyzos et al., Fertil Steril 2013

Anti-Müllerian hormone for the assessment of ovarian response in GnRH-antagonist-treated oocyte donors. Polyzos et al., RBMonline 2013• Retrospectively examined patients files• Recorded AMH values• Checked who were the patients pregnant and not

pregnant

Cohort studies- prospective

(?)

(?)

YES

NO

Exposure

Investig

ator

Disease-outcome

e.g. AMH values

e.g. Pregnancy outcome

Retrospective cohort

Example of a prospective cohort

The predictive value of circulating anti-Müllerian hormone in women with polycystic ovarian syndrome receiving clomiphene citrate: a prospective observational study. Mahran et al., JCEM 2013• Prospectively enrolled patients before treatment begins• Recorded AMH values• Waited till the cycles finished to evaluate how many

responded

Clinical trials

Types of Clinical Trials

• Randomized versus non-randomized• Treatment arm -- with or without a control arm• Testing the safety and effectiveness of a drug or

intervention

Clinical Trials: Phases I - IV

• Phase I

– Safety-testing small groups of 10 to 15 patients

• Phase II

– Pilot studies to confirm effectiveness

of the drug - less than 100 patients

Clinical Trials: Phases I - IV

• Phase III

– Large groups of patients for statistical confirmation of effect and incidence of side-effects > 100 patients

• Phase IV

– Post marketing studies - fine tuning, and new rare findings from a very large population

LEVEL I Evidence

Randomized Clinical Trials

Randomized Controlled Studies

Description:

• After assessment of eligibility and recruitment, but before the intervention to be studied begins, randomly allocated to receive one or other of the alternative treatments under study

Randomized Controlled Studies

Advantage:

• RCTs are considered by most to be the most reliable form of scientific evidence in the hierarchy of evidence that influences healthcare policy and practice

Randomized Controlled Studies

Disadvantages:

• Costs

• Time

• Rare events

Designing a clinical and especially a randomized trial …

… Is it that easy?

It can be...

...possibly the most important part of your trial

The Study Protocol

Proper Study Protocol

• Research question--rationale• Exact study design• Inclusion-exclusion criteria

• Randomization procedure, allocation concealment, blinding

• Timing of blood sampling and monitoring• Clearly defined interventions

Proper Study Protocol

• Primary outcomes

• Appropriate statistical analysis

• Feasibility of the study

• Data management

• Ethical considerations

Research Question and Hypothesis

• Simple – one question and one answer

• In accordance with the available evidence

• Ask yourself:

– Why is such a study valuable?

– Can it change clinical practice?

Study Design

• Parallel group

– Each participant is randomly assigned to a group, and all participants receive (or not), an intervention.

• Crossover

– Over time, each participant receives (or not), an intervention in a random sequence.

Study Design

• Cluster

– Pre-existing groups of participants, (e.g. villages, schools) are randomly selected to receive, or not to receive, an intervention

Study Design (3)

• Factorial– Each participant is randomly assigned to a group that

receives a particular combination of interventions or non-interventions

– (e.g., group 1 receives vitamin X and vitamin Y, group 2 receives vitamin X and placebo Y, group 3 receives placebo X and vitamin Y, and group 4 receives placebo X and placebo Y)

Population to Include..

• Clearly defined• Easy to recruit• Easy to follow • Sample presumed to represent population

Unclear Population…Not Replicable Results

• 47 randomized trials using 41 definitions for poor ovarian responders

• No more than 3 trials used the same definition• Even trials from the same research group used a

different definition

Who are the poor ovarian responders?

Randomization Procedure (1)

• Simple randomization• Block randomization• Computer generated list

Randomization Procedure (2)

Generation of allocation sequences• Adequate if sequences are suitable to prevent

selection bias: random numbers generated by computer, table of random numbers, drawing of lots or envelopes, tossing a coin, shuffling cards, throwing dice, etc.

• Inadequate if sequences could be related to prognosis and thus introduce selection bias: case of record number; date of birth; day, month, or year of admission; etc.

Juni P et al., BMJ 2001

Randomization and Concealment of Patient Allocation

• The procedure for protecting the randomization process so that the treatment to be allocated isnot known before patient is entered into the study

• Methods to ensure– sequentially numbered, opaque, sealed envelopes

(SNOSE)

– sequentially numbered containers

– pharmacy controlled randomization

– central randomization

Juni P et al., BMJ 2001

Randomization and Concealment of Patient Allocation (continued)

Generation of allocation sequences• Adequate if sequences are suitable to prevent

selection bias: random numbers generated by computer, table of random numbers, drawing of lots or envelopes, tossing a coin, shuffling cards, throwing dice, etc.

• Inadequate if sequences could be related to prognosis and thus introduce selection bias: case of record number; date of birth; day, month, or year of admission; etc.

Juni P et al., BMJ 2001

Randomization and Concealment of Patient Allocation (continued)

Generation of allocation sequences (cont): • Inadequate if patients and investigators enrolling

patients can foresee assignments and thus introduce selection bias: procedures based on inadequate generation of allocation sequences, open allocation schedule, alternation and other unsealed or non-opaque envelopes, etc.

Juni P et al., BMJ 2001

Randomization and “Blinding” Status of Subjects

• Procedures that prevent study participants, caregivers, or outcome assessors from knowing (by randomization) which intervention was received

• Types– Single-blind– Double-blind– Open Label

Strength of Randomization

• Inadequate if patients and investigators enrolling patients can foresee assignments and thus introduce selection bias: procedures based on inadequate generation of allocation sequences, open allocation schedule, alternation and other unsealed or non-opaque envelopes, etc.

Juni P et al., BMJ 2001

Monitoring Patients

First Consultation

Stimulation Day

Assessment 1 2 3 4 6 7 8 10 Day of hCG

OPU ET OPU +  14 Days

ET + 35‑42 Days

ET +  49-56 Days

Cycle Discon

Clinical examination: Vital signs and Weight X

Pregnancy Test X X XLaboratory exams (local lab):

- Chemistry/ Hematology X

- FSH, LH, E2, P X X X X X X X X - AMH XUSS X X X X X X XART Procedures X XPrevious and Concomitant Medication

Whenever previous or concomitant mediation is used

(S)AEs Whenever an (S)AE occursCycle Summary At cycle discontinuation or completionSubject Status At trial discontinuation or completion

Clearly defining interventions

ADMINISTRATION DAY

MEDICATION 1 2 3 4 5 6 7 8 10

Investigational Group

Drug A X X X X X

Drug B X X X X X X X X

Reference Group

Drug C X X X X X

Drug D X X X X X X X X

Both Groups

Drug E X

Choosing Primary Outcomes

• Select a primary

• Exact timing when the primary outcome is measured

• Secondary outcomes may also be selected

• Do not select surrogate outcomes, e.g., pregnancy – not oocytes, nor embryos

Juni P et al., BMJ 2001

Calculating Sample Sizes

• Power: What sample size needed? Calculation will be based on:– Expected 80% power, level of significance P< 0.05– Estimated sample recruitment based on previous

evidence.– Do not make your sample size based on unrealistic

assumptions.

• During the protocol formulation describe the statistics to be used.

Performing Statistical Analysis

Who is going to be the “person behind your numbers”?

• Crucial part of any clinical trial– Wrong analysis = wrong results– Improper test = not valid study– A statistical mistake can jeopardize

years of work

Determine Feasibility of Conducting the Study

• Are resources available (funding, personnel)?

• Can an adequate number of patients be recruited?

• Will it be easy to follow your patients (subjects)?

Data Management

Case report forms (CRF)

Uniform templates for extracting data

Ethical Considerations

• Institutional Review Board (IRB)

• ERB approval (Ethical Review Board)

• Inform consents

• Trial registration

• Sponsorship Acknowledgement

11. Ethical considerations

• IRB approval • Inform consents• Acceptance from National competent authorities• Trial registration• Sponsorship

Institutional Review Board (IRB) Approval

• All institutions should have (by law or regulation) an IRB to evaluate whether it’s ethical to conduct a given study

• Submit your protocol and wait for acceptance prior conducting a trial

• Follow institutional instructions and explain in detail the rationale, population, interventions, and goals of the study

Inform Your Patients Properly…. Obtain Their Written Consent…..

• Very detailed information for the treatment (drugs, duration, procedures)

• Current gold standard• Expectation that the new treatment may show

a difference• Avoid scientific terms … let them understand

(6th - 8th grade level)• List potential side effects and who takes

responsibility• Obtain their signature, usually requiring a witness

Acceptance from National competent authorities

• Regulatory authorities responsible for human medicines

• Only for medicines or devices• It is ILLEGAL to perform a trial with a medicinal

product without having acceptance from your National competent authority

Register Your Trial !

• After approval of relevant IRB, register your trial in a trial registry - (e.g. clinicaltrials.gov)

• For publication, most journals require trial registration prior the conduction of the study

Declare Any Indirect or Direct Funding From the Industry

• ICJME suggests reporting any potential conflict(s) of interest related (or not related) to the study, err on the conservative side

• Industry funding should be reported

Institutional Review Board (IRB) approval

• All institutions should have (by law) an IRB to evaluate whether it is ethical to conduct the study

• Submit your protocol and wait for acceptance prior to conducting a trial

• Explain in detail the rationale, the population, the interventions and the goals of the study

Inform your patients properly…. Get their written consent…..

• Very detailed information for the treatment (drugs, duration, procedures)

• What is the current gold standard• Why do you expect the new treatment to show

difference• Do not use scientific terms…let them understand• Inform about potential side-effects and who is

taking any liability in such a case• Obtain their signature

Register your trial in a public trial registry (1)

• After approval of IRB register your trial in a trial registry

• Most journals require trial registration prior to the conduction of the study

Register your trial in a public trial registry (2)

AVAILABLE REGISTRIES FOR CLINICAL TRIALS• Australia and New Zealand's (ANZCTR) (http://www.anzctr.org.au)

• Brazilian Clinical Trials Registry (ReBec) (http://www.ensaiosclinicos.gov.br)

• Chinese Clinical Trial Registry (ChiCTR) (http://www.chictr.org)

• Clinical Research Information Service (CRiS), Republic of Korea (http://cris.cdc.go.kr)

• Clinical Trials Registry - India (CTRI) (http://ctri.nic.in)

• Cuban Public Registry of Clinical Trials(RPCEC) (http://registroclinico.sld.cu)

• EU Clinical Trials Register (EU-CTR) (https://www.clinicaltrialsregister.eu/)

Register your trial in a public trial registry (3)

AVAILABLE REGISTRIES FOR CLINICAL TRIALS• German Clinical Trials Register (DRKS) (http://www.drks.de)

• Iranian Registry of Clinical Trials (IRCT) (http://www.irct.ir/)

• Japan's UMIN-CTR (http://umin.ac.jp)

• The Netherlands, Trialregister.nl

• The United States, ClinicalTrials.gov

• The International, ISRCTN.org

• Pan African Clinical Trial Registry (PACTR) (http://www.pactr.org/)

Declare any indirect or direct funding from industry

• ICJME suggests reporting of any potential conflict of interest related or not to the study

• Industry funding should be reported

Thank you

Randomized Clinical Trials