studies other than rct - internal.must.edu.eg in biomedical... · answer the novalgin® question...

Studies Other Than RCT

Dr. Sherif El Ghandour

Drug Information Center

Objectives

� Describe different types of studies in the literature other than RCT.

� Describe characteristics of observational trial design.

� Describe methods of study categorizations and ranking.

� Differentiate between literature reviews and meta-analysis

Why not all the studies are RCT?

� When RCT is not feasible, rare outcome. (Case control)

� When RCT is not ethical, cardiotoxicity of NSAIDs. (cross sectional), (case control)

� No money.

Types (broad classification) of clinical

studies:� Experimental.

� Observational.

� Reviews.

Types of clinical studies:

� Experimental

� RCT.

� Observational

� Reviews

Randomized Controlled Clinical Trials(The cornerstone of evidence based

practice)


� Experimental

� RCT.

� N-of-1 trials.

� Observational

� Reviews

Compare effects of drug to control during multiple observational periods

in a single patient.


� Experimental

� RCT.

� N-of-1 trials.

� Stability studies.

� Observational

� Reviews

Evaluate stability of drugs in various preparations, such as ; ophthalmic , IV, topical or oral


� Experimental

� RCT.

� N-of-1 trials.


� Bioequivalent studies.

� Observational

� Reviews

Assess the bioequivalecy of 2 or more products.


� Experimental

� RCT.

� N-of-1 trials.


� Bioequivalent studies.

� Programmatic research.

� Observational

� Reviews

Determine the impact and / or economic value of clinical

service


� Experimental

� Observational

� Cohort studyDetermine association between various factors and disease state development.


� Experimental

� Observational

� Cohort study

� Trohoc study (case control)

Determine association between disease states and exposure to

Various risk factors


� Experimental

� Observational

� Cohort study


� Cross sectional study

Identify prevalence of characteristics of disease in

populations


� Experimental

� Observational

� Cohort study



� Case study, case report or case series.

Report observations in a single patient or series of

patients


� Experimental

� Observational

� Cohort study




� Survey search

Study incidence, distribution, and relationships of sociologic and

psychological variables by using a questionnaire for various

populations


� Experimental

� Observational

� Cohort study




� Survey research.

� Post marketing surveillance.

� Reviews

Evaluate use and adverse effect associated with newly approved drug

therapies


� Experimental

� Observational

� Reviews

� Narrative reviewNonsystematic, subjective

summary of data from multiple studies.


� Experimental

� Observational

� Reviews

� Narrative review

� Systematic reviewSystematic, qualitative and objective summary of data

from multiple studies.


� Experimental

� Observational

� Reviews

� Narrative review

� Systematic review

� Meta-analysis.

Combines, statistically evaluate, and summarizes data from multiple studies.

Experimental (Clinical) studies

� Determine cause and effect relation.

� Contain intervention that is introduced or omitted by the investigator.

N- of -1 trial

� Crossover study conducted in a single subject

� It can identify responders from non responders.

� Very helpful if the Rx is;

� For symptomatic relief

� In chronic disease

� For drugs with short t1/2

Programmatic research

� Studies the impact and economic value of programs and services provided by pharmacists in community and institutional setting.

� Pharmacists have demonstrated that they can improve drug therapy

� Effectiveness

� Efficiency

� safety

Observational studies

� Do not involve intervention.

� Evaluate questions based on less rigidly controlled practice conditions than those used in experimental studies.

� Subject groups are based on absence or presence of a disease or exposure with observation being made and recorded regarding patient characteristics.

Cohort studies

� Synonyms; follow up, longitudinal or incidence study.

� Prospective.

� Disease free subject population.

� Exposed to certain factor of interest.

� Population are then divided into 2 groups

� Exposed

� Unexposed

Cohort studies

2 X 2 table to calculate prevalence

and relative risk (RR)

C+D

2000

D

1970

C

30

Study of cohort (factor absent-fixed)

No-Formaldehyde

A+B

2000

B

1800

A

200

Study of cohort (factor present-fixed)

Formaldehyde

Disease/Outcome

Absent

Disease/Outcome Present

Computations:

A + C

A + B + C + D

=Outcome Incidence or Prevalence

C / (C + D)PNF =Rate of outcome in people

without the factor

A / (A + B)PF =Rate of outcome in people

with factor

Prevalence of respiratory disease = 230 / 4000 % = ~ 0.06%

Computations:

A / (A + B)

C / (C + D)

=

Disease present/people with factor

Disease present/people without factor=

rate of disease in people with factor

rate of disease in people without factor

Relative Risk =

RR

Relative Risk (RR) = 200 /2000 ÷ 30/2000 = ~ 6.7

This

Computations:

A / (A + B)

C / (C + D)

=





Relative Risk =

RR

Relative Risk (RR) = 200 /2000 ÷ 30/2000 = ~ 6.7

This

This means that exposure to

formaldehyde increases the risk of developing respiratory disease ~ 7 times..

Computations:

A / (A + B)

C / (C + D)

=





Relative Risk =

RR

Gives an idea of the magnitude of an effect

however without precision

Critical Thinking

� If you quit smoking before the age of 50 you will reduce risk of dying in the next 15 years by 50%.

� CDC 1990

Case Control Studies (TROHOC)

� Synonyms; case history, retrospective studies.

� Offer an epidemiologic research alternative to cohort studies.

� Suitable in cases of

� Large number of subjects are needed.

� No money.

� No time for follow up as in cohort.

� Infrequent or rare disease.

Case Control Studies

Computations:

WHAT are the ODDs to have respiratory disease and being exposed to formaldehyde? 20:180 = 20 ÷ 180 = 20 / 180

What are the ODDs not to have respiratory illness although being exposed to formaldehyde? 5/195

What is the risk rate (ODD’s Ratio) of having respiratory if you were exposed to formaldehyde for the last X years?

D

195

C

180

Study of cohort (factor absent-fixed)

No-Formaldehyde

B

5

A

20

Study of GROUP (factor present-fixed)

Formaldehyde

Disease/Outcome

Absent

Disease/Outcome Present

Computations:

OR = 20/180 ÷ 5/195

= 20/180 x 195/5 = 20 x 195 = ~ 4.5

180 x 5

Computations:

OR = 20/180 ÷ 5/195 = 20/180 x 195/5 = 20 x 195 = (~ 4.5)

180 x 5

We can say that there is increase risk 4 times for developing respiratory illness with exposure to formaldehyde than in case of no exposure.

Why has Novalgin® been band allover

the world but not in Egypt?

Critical thinking

� The International Agranulocytosis and Aplastic Anemia Study (IAAA study)

� a population- based case-control study conducted in Europe and Israel.

� Analgesic use in the week before the onset of illness was compared between 221 cases of agranulocytosisand 1425 hospital controls.

� Among analgesics, dipyrone was associated with the highest rate ratio (Odds Ratio) estimate for agranulocytosis (= 23.7)

Critical thinking

� However indomethacin, and butazones (phenylbutazone and oxyphenbutazone) were also associated with agranulocytosis in rate ratio of 8.7 and 3.8 respectively.

� The study at the end suggested that the risk for agranulocytosis is as low as 1.1 cases per million users.

� This study had vastly varying risks in different countries that ranged from 0.9 in Budapest and up to 33.3 in Barcelona.

Critical thinking

� Consumption and frequency of use of dipyrone differs from country to country and some populations may have increased genetic susceptibility to agranulocytosis.

Answer

� The Novalgin® question was not properly asked.

� Dipyrone is available both as a single and multiple ingredients

Single-ingredient Preparations

Argentina; Austria; Belgium; Brazil; Chile; Czech Republic; Germany; Hungary; India; Israel; Italy; Mexico; Netherlands; Portugal; Russia; Spain; Switzerland; Thailand; Venezuela.

Multi-ingredient Preparations

Argentina; Austria; Belgium; Brazil; Chile; Czech Republic; Finland; France; Hungary; Italy; Mexico; Russia; South Africa; Spain; Thailand; Venezuela.

Cross Sectional Studies

� Data are collected and evaluated at a single point in time (snapshot).

� Hypothesis generating not hypothesis testing.

� Examples

� Surveys

� Opinions

� Situations At fixed point of time

� Descriptive studies

� Diagnosis of a disease.


� A survey of smokers (questionnaire was taken once).

� The questions contained in this survey focus on smoking habits over the past 10 years.

� Is it still cross sectional study?


� Advantages

� Quick

� Easy to perform

� Useful for measuring current health status or trends

� Problems:

� Data collection

� Transient effects


� Advantages

� Quick

� Easy to perform

� Useful for measuring current health status or trends

� Problems:

� Data collection

� Transient effects

A professor chooses to have students evaluate a course after difficult exam.

Cross Sectional Studies (Example)

Medication Adherence Following Coronary Artery Bypass Graft Surgery: Assessment

of Beliefs and Attitudes

Ann Pharmacother 2008;42:192-9


� BACKGROUND:

The medication management of patients following coronary artery bypass graft (CABG) surgery may include;

� antiplatelet agents,

� b-blockers,

� angiotensin- converting enzyme inhibitors,

� and statins.

However, poor adherence is common, and patient attitudes and beliefs play a role in adherence.


� OBJECTIVE:

� To evaluate the association between self-reported adherence and the beliefs patients have about cardiovascular medicines used after CABG.


METHODS: � Adults were surveyed 6–24 months following CABG.

� The validated Beliefs about Medicines Questionnaire (BMQ) assessed attitudes concerning � Specific Necessity (without the medicine I will die)

� Specific Concerns (I am worried to be dependent on the Rx)

� General Harm (most medicines are poisonous)

� General Overuse of medicines ( natural remedies are safer)

� The validated medication adherence scale assessed self-reported adherence.

Cross Sectional Studies (Example)RESULTS:

� 132 / 387 patients responded = (34%) of the target population.

� Non-participants were more likely to be female and have undergone 1- or 2- vessel CABG procedures compared with 3- or 4-vessel procedures.

� Adherent behavior was reported in 73 of 132 patients (55%).

� The average period between CABG and the survey was 16 months.

Cross Sectional Studies (Example)RESULTS:

� Non-adherent patients were in stronger agreement on the General Overuse (p = 0.01) and General Harm (p = 0.04) scales.

� The adjusted odds of adherent behavior were significantly lower, with an increasing General Overuse score (OR 0.83; 95% CI 0.72 to 0.95; p = 0.007)

� Annual income of $50,000 to $100,000 relative to less than $20,000 (OR 0.36; 95% CI 0.14 to 0.91; p = 0.031).

� A living status of “alone” compared with “with adults and no children” (OR 0.20; 95% CI 0.06 to 0.65; p = 0.007).

� The odds ratio of self-reported adherence was higher with increasing age (OR 1.05; 95% CI 1.01 to 1.09; p = 0.023).

Case studies (Case Reports) and Case

Series

� Case Study = Case Report dealing with a single patient.

� Case series deal with group of patients

� Both have no control or comparison groups.

� Are retrospective.

� Difficult to interpret.


Series ExampleAllopurinol augmentation for poorly responsive

schizophrenia

CASE REPORTS

� A 43-year-old male with schizophrenia since the age of 16 years and 19 psychiatric admissions, presented persistent auditory hallucinations, paranoid delusions, hostility, apathy, social and emotional withdrawal.

� He had been treated with haloperidol up to 15 mg, levomepromazine up to 1200 mg, or fluphenazine depot up to 50 mg per month. (unsatisfactory response).

� Augmentation strategies with carbamazepine or valproate were unsuccessful.

Lara et al, Int Clin Psychopharmacol. 2001, 16 (253-257).


Series Example� Before allopurinol, he was on 500 mg of levomepromazine with

Brief Psychiatric Rating Scale (BPRS.) score of 64.

What happened?� Improvement of both positive and negative symptoms was

observed within the first week of allopurinol addition.

� BPRS was 30 after 4 weeks and 28 after 8 weeks of treatment.

� His family reported that his hostile and autistic behaviors ceased and he started helping with domestic tasks, doing some shopping by himself, visiting his sisters and joining meetings of the extended family.

� Improvement of sleep was also reported and side-effects were not observed.

� Lara et al, Int Clin Psychopharmacol. 2001, 16 (253-257).


Series Example

� The authors in the previous study used add-on allopurinol 300 mg once a day in 11 schizophrenic patients (DSM-IV), who were poorly responsive to conventional treatment, with unchanged antipsychotic dosages.

� Among these, four had no clinical response, two showed mild symptom improvement.

� Five presented clinically relevant improvement evaluated by Clinical Global Impression.

� They only reported the best 2 cases of them.


Series another Example

Richard Gomberg (2007), reported the following case;

� A 22 year old woman with a 4 year history of schizophrenia, chronic paranoid type.

� She was on a stable regimen of clozapine 500 mg and ziprasidone180 mg a day.

� She was in a full remission, without any of her previous hallucinations and paranoia, when she developed an acute monoarticular arthritis, and her primary care doctor diagnosed her with gout.

� The patient had a strong family history of gout (both her father and grandfather had gout).


Series another Example� her primary care doctor prescribed her allopurinol 300 mg at

night.

� Within an hour of her first dose of allopurinol she had a recurrence of her typical auditory hallucinations and paranoia, which lasted until she fell asleep. The next morning she awoke without any psychotic symptoms.

� Each of the next two nights she took the allopurinol with the same recurrence of symptoms which again resolved by the following morning.

� Richard Gomberg. Schizophrenia Research Volume 93, Issues 1-3, July 2007, Page 409



� After three nights, she stopped taking allopurinol and her symptoms did not return again.

� She had no other medication changes or environmental stressors which could explain her relapse.

� When she was seen at her regularly scheduled appointment, she was able to describe in detail the symptoms which she had experienced on those three evenings, but the symptoms had completely resolved, and she had no current signs of psychosis or thought disorder.




Conclusion

� It is possible that in some patients allopurinol may have a negative affect on their mental status.

� Patients with schizophrenia who are treated with allopurinol should be carefully monitored for recurrence or worsening of their symptoms.


What do you Think?

Post-marketing Surveillance studies

� Also called Phase IV studies.

� Can identify rare adverse effects.

� Reason for drug withdrawal.

� Design can take several forms� Cross sectional

� Case control

� Cohort

� Spontaneous report of adv. effects.

� RCT

RCT for the previous example question

Akhondzadeh et al 2005 conducted RCT.

� The purpose of their investigation was to assess the efficacy of allopurinol as an adjuvant agent in the treatment of chronic schizophrenia in an 8-week double blind and placebo controlled trial.

� Eligible participations in the study were 46 patients with schizophrenia. All patients were inpatients and were in the active phase of the illness, and met DSM-IV criteria for chronic schizophrenia.

� Patients were allocated in a random fashion, 23 to haloperidol 15 mg/day plus allopurinol 300 mg/day and 23 to haloperidol 15 mg/day plus placebo.

� Akhondzadeh et al Prog Neuropsychopharmacol Biol Psychiatry. 2005 Feb;29(2):253-9.

What do you Think?

� The combination of haloperidol and allopurinol showed a significant superiority over haloperidol alone in the treatment of positive symptoms, general psychopathology symptoms as well as PANSS total scores.

� The means of Extrapyramidal Symptoms RatingScale for the placebo group were higher than in the allopurinol group over the trial, and the differences were significant in weeks 6 and 8.

� A significant difference was observed between the overall mean biperiden dosages in two groups.

� Akhondzadeh et al Prog Neuropsychopharmacol Biol Psychiatry. 2005 Feb;29(2):253-9.

What do you Think?

� The results of this study suggest that allopurinol may be an effective adjuvant agent in the management of patients with chronic schizophrenia.

� Nevertheless, results of larger controlled trials are needed, before recommendations for a broad clinical application can be made.

� Akhondzadeh et al Prog Neuropsychopharmacol Biol Psychiatry.2005 Feb;29(2):253-9.

Review ArticlesPublications which attempt to combine results from

multiple studies.

Consisting of analysis and interpretation of previously conducted research studies.

Quiz:

Are the Review articles

� Primary

� Secondary

� Or Tertiary references?

Review Articles

� Narrative Review

� Systematic Review

� Meta-Analysis

Review Articles


� Lacks systematic methods.

� Citations are influenced by discipline and nationality

� Influenced by clinical judgments


� Meta-Analysis

Review Articles


� Systematic Review� Qualitative

� Gives summary of results of primary studies

� Thorough search in more than 1 database.

� Should exclude poorly controlled non randomized, unblinded studies

� Does not combine statistically the results of the studies.

� Meta-Analysis

Review Articles



� Meta-Analysis� Address clearly defined and focused clinical

question.

� Thorough search in different databases

� Only include studies according to predefined criteria

� Rigorous and objective analysis of data

� Results are statistically evaluated.

The same Example of allopurinol for

Schizophrenia (Systematic review)� OBJECTIVE: To review the available literature evaluating the

effectiveness of allopurinol for poorly responsive or treatment refractory schizophrenia.

� DATA SOURCES: Searches of MEDLINE (1966–October 2006), the Cochrane Library, and International Pharmaceutical Abstracts (1970–October 2006) were conducted using the terms allopurinol and schizophrenia. Limits were set to select studies conducted in humans.

� STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated. All case reports or clinical trials located were included in the review.

Buie et al. (2006). Ann Pharmacother 40 (12): 2200.


Schizophrenia (Systematic review)Discussion

There are several limitations;

1. Both of the trials are small sample size.

2. Both are short term < 8 weeks

3. The crossover study allowed treatment with other drugs which may lead to misinterpretation of the effect of allopurinol.

4. None of the studies used the gold standard Rx (Clozapine).

5. Majority of the literature that supports the purinergic hypothesis of schizophrenia are by Lara et al.



Schizophrenia (Systematic review)

CONCLUSIONS:� Clinical trials show that adjuvant allopurinol may provide benefit to

patients who are poorly responsive to current treatments for schizophrenia.

� Allopurinol is well tolerated by most patients. However, larger, randomized clinical trials need to be performed to determine themagnitude of this benefit, whether allopurinol should be routinely used as adjuvant therapy to antipsychotics, and which patient population is most likely to benefit from allopurinol use.

� For patients with limited options, allopurinol in doses of 300 mg once or twice daily may improve psychotic symptoms, especially refractory positive symptoms.


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