CLINICAL TRIAL DESIGN, ANALYSIS AND REPORTING FROM THE DOOR OF SPONSOR OR CRO.

 


Whatever the mode of randomization is, it is ensured that the pattern of assignment of control or experimental drug within a group of patients cannot be guessed at any point. It is recommended that the statistician who generated the randomization codes does not get involved in the IA or the final analysis of the experimental data[18,19].


Factorial design: A simple factorial design would have one group testing therapy (A), another testing therapy (B), A third group testing (A) and (B) combined and a control group testing neither (A) nor (B). Factorial designs are considered an efficient way to test medicines in combination, but their results are not always easy to interpret[1,2].


Cross Over: In a cross over trial, each participant get both treatment being treated. Some participants are assigned at random to receive drug (A) and later drug (B). Other receive (B) then (A). To produce valid results, the effect of the first drug must end before the 2nd drug taken, and vice versa. This recruitment can hard to satisfy andis one reason cross over trials are not used[2].


DIFFERENT PHASES OF TRIALS:
*  Phase – I

*  Phase- II

*  Phase- III

*  Phase- IV


Phase – I:   Early use of drug. Mainly  aimed in establishing safety and toxicity limits.  Study subjects often normal. No control groups. Usually open level[20].

Phase I design:  Based on tradition, not so much on statistical theory. Dose escalation is reach maximum tolerated dose (MTD).  Dose escalation often based on Fibonacci series i.e 1 2 3 5 8 13….

Let’s see:
[1] Enter 3(5) Patients at a given dose.

[2] If no toxicity, go to next dosage and repeat step 1.

[3] a.  If 1 patient has serious toxicity, and 3 more patients at that dose (go to 4)
b. If 2/3 have serious toxicity , consider MTD.

[4] a. If 2 or more of 6 patients have toxicity, MTD reached.
b. If 1 of 6 has toxicity, increase dose and go back to step1.

Phase- II:  Proof of principal stge. Intervention studied in patients with diseases. Dose  findings. More  safety data.  Sometimes combined with Phase- I.

Let’s see:  LetX% = 20% i.e want to check if drug likely to work in at least 20% of patient.

[1] Enter 14 Patients

[2] If 0/14 responses – No responses are observed trial is terminated.

[3] 1+/14 responses. Add 15-40more patients.

[4] Estimate response rate.

Phase- III: Randomized controlled trial. Double blind whenever possible.  More patients. Multi center. Ongoing safety data.

Phase III design:   Comparative study : Experimental Vs Control group

Phase- IV:  Post approval studies. Further exploration of Intervention - -New Indications or new uses of drugs.

DATA ANAYLSIS:
Record the outcome(s) of Interest. Compare the data for each intervention group. Derive conclusions.

CLINICAL TRIAL REPORTING:
A written description of a trail/Study of any therapeutic, prophylactics or diagnostic agent conducted in human subjects, in which the clinical and statistical description presentation and analyses are fully integrated in to single report[6].

CONCLUSION:
Research and the Clinical trial is a fundamental of modern medicine. In fact, the Clinical trial is the medical invention that has contributed to nearly all of the life saving medicine.

These medicines have: Added 10yrs to our life expectancy, Made organ transplant possible/ Diabetes manageable conditions. Extended the life expectancy of AIDS patients and prolonged the lives of millions of Cancer patients.

REFERENCES:
[1] Duolao Wang, Ameet Bakhai, ‘’Practical guide to  Design, Analysis and Reporting’’, Published by Remedica common wealth house,UK: 2-3.
[2] Professor Janet Darbyshire, Sir Iain Chalmers, Dr Sophie Petit-Zeman, Roger Wilson, Dr Marianne Miles, Dr Matthew Hallsworth ‘’Understanding Clinical Trial- Booklet Version-2 (October2010)’’ .
[3] crncc.nihr.ac.uk/Resources/NIHR%20CRN%20CC/Documents/Brochures/Understanding%20Clinical%20Trials%20Booklet%20-%20crystal%20mark.pdf
[4] en.wikipedia.org/wiki/Clinical_trial
[5] clinicaltrials.gov/ct2/about-site/history
[6] fda.gov/downloads/Drugs/NewsEvents/UCM251958.pdf
[7] cel.sfsu.edu/clinical-trials/
[8] Information from the NHS about clinical trials
ibrary.nhs.uk/trials
[9] MRC Clinical Trials Unit
ctu.mrc.ac.uk/about_clinical_trials.aspx
[10] Database of ongoing and completed clinical trials in the UK
controlled-trials.com/mrct
[11] UK Clinical Trials Gateway
controlled-trials.com/ukctr
[12] Directory of clinical trials funded by the pharmaceutical industry
ifpma.org/clinicaltrials
[13] The U.S. National Institutes of Health ClinicalTrials.gov
clinicaltrials.gov
[14] Opportunities for public involvement in clinical research  
peopleinresearch.org
[15] Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.(RENAAL) N Engl J Med. 2001;345:861–9.
[16] Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): A multicentre randomised controlled trial. Lancet.2005;366:895–906.  
[17]. Barst RJ, McGoon M, McLaughlin V, Tapson V, Rich S, Rubin L, Wasserman K, Oudiz R, Shapiro S, Robbins IM, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003;41:2119–2125.
[18] Center for Drug Evaluation and Research. Medical review of application #22–081: Ambrisentan. Center for Drug Evaluation and Research; 2007.
[19] McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, Badesch DB, Barst RJ, Hsu HH, Rubin LJ. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;174:1257–1263.  
[20] Sue-Jane Wang, Clinical Trial design/ ‘’CDER small Business Assistance Clinical Trial forum’’April 21, 2011.

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