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Statistics and clinical trials for PG students

Statistics and clinical trials for PG students

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  • - Patients enrolled on the study had to meet the following inclusion criteria: -- locally advanced, non-metastatic, measurable SCCHN -- stage lll or lV disease -- Karnofsky performance status of > 60%. -- normal hematopoietic, hepatic and renal function -- no evidence of distant metastasis -- medically able to withstand a course of definitive radiotherapy -- no previous malignancy, no chemotherapy within the past 3 years and no surgery or radiotherapy for head and neck cancer. - Tumor EGFR expression was not an entry requirement. 1. Bonner J, Harari P, Giralt J, et al. N Eng J Med 2006;354:567-578
  • - Given the high correlation of EGFR expression with poor prognosis in patients with SCCHN and the fact that pre-clinical studies demonstrated an enhancement of the effect of RT when combined with ERBITUX, a phase l study was undertaken by Robert et al. to assess the interaction of ERBITUX and RT in patients with locally advanced, unresectable SCCHN. 1. Robert F, Ezekiel MP, Spencer SA, et al. J Clin Oncol 2001;19:3234-3243
  • - A high percentage of head and neck tumors express the EGFR,[1] therefore, this tumor type was selected to analyze the clinical efficacy and safety of ERBITUX.  - In this phase I study,[2] patients with previously untreated unresectable, locally advanced (stage III/IV) SCCHN cancer received: -- ERBITUX at an initial dose on day 1 ranging from 100 to 500 mg/m 2 , followed by weekly maintenance doses of 100, 200 or 250 mg/m 2 for eight weeks -- conventional radiotherapy (RT) (70.0 Gy at 2.0 Gy/day) or hyperfractionated RT (76.8 Gy at 1.2 Gy/bid) starting on day 8. - The choice of conventional versus hyperfractionated RT was based on physician preference. - Patients were treated in groups of 3 or more per ERBITUX dose level in a dose-escalating fashion. 1. Grandis JR, Melhem MF, Barnes EL, Tweardy DJ. Cancer 1996;78:1284-1292 2. Robert F, Ezekiel MP, Spencer SA, et al. J Clin Oncol 2001;19:3234-3243
  • - Bonner et al conducted one of the largest studies in this setting, in which patients with measurable locally advanced SCCHN, assessed by a comprehensive head and neck examination and computed tomography (CT) or magnetic resonance imaging (MRI) scans of the head and neck and a chest radiograph, were randomized to receive either RT alone for 7-8 weeks, or RT plus weekly ERBITUX. - RT was administered according to one of three fractionation regimens, according to investigator preference: once daily 70 Gy, 35 fractions; twice daily 72-76.8 Gy, 60-64 fractions; or concomitant boost 72 Gy, 42 fractions. - Patients were stratified by: -- Karnofsky performance status 60-80% versus 90-100% -- N0 versus N+ -- T1-3 versus T4 -- RT fractionation regimen. - Erbitux was administered as a 400 mg/m² initial dose 1 week prior to RT followed by subsequent weekly doses of 250 mg/m². - Patients were followed for a total of 5 years, by physical examination and radiographic imaging (every 4 months for the first 2 years and then every 6 months for the next 3 years). 1. Bonner J, Harari P, Giralt J, et al. N Eng J Med 2006;354:567-578
  • - A total of 171 of the 424 patients (40%) enrolled in the Bonner et al. study had hypopharyngeal and laryngeal cancer. - Patients were randomized to receive either: -- ERBITUX plus radiotherapy (n=93) or -- radiotherapy alone (n=78). - Patients who underwent no surgery, or lesser surgeries, were censored at death or the date of last contact, and the hazard ratio was calculated by Cox regression. 1. Bonner J, Harari P, Giralt J, et al. J Clin Oncol 2005;23(16S):Abstract 5533. Updated information presented at ASCO
  • - The primary endpoint of the study was locoregional control (LRC), which was defined as the absence of locoregional disease progression at scheduled follow-up visits. Investigator-generated data were assessed by an independent review committee using prospectively developed guidelines. - The secondary endpoints were: -- overall survival -- progression-free survival -- overall response rate -- safety. - Efficacy evaluations were made on an intention-to-treat basis. 1. Bonner J, Harari P, Giralt J, et al. N Eng J Med 2006;354:567-578
  • - A total of 424 patients from 73 centers were randomized to either radiotherapy alone (n=213) or ERBITUX plus radiotherapy (n=211). - Approximately two-thirds of patients in each arm had a Karnofsky performance status of 90-100% and the most common primary tumor site was the oropharynx. - Three-quarters of patients in each arm had stage IV disease. The majority of patients (approximately 70% in each arm) had T1-3 disease and around 80% in each arm had node-positive disease. - The two treatment arms were well balanced with respect to radiotherapy dose, fractions received, post-radiotherapy neck dissection and secondary cancer therapy. 1. Bonner J, Harari P, Giralt J, et al. N Eng J Med 2006;354:567-578
  • - In terms of treatment, the most commonly used radiotherapy fractionation scheme was concomitant boost radiotherapy (56%), followed by once daily (26%) and twice daily (18%) fractionation. - The addition of ERBITUX to radiotherapy statistically significantly prolonged the median duration of locoregional control by 9.5 months, from 14.9 to 24.4 months (hazard ratio [HR] 0.68, 95% CI 0.52, 0.89; p=0.005). - The effects of treatment on locoregional control according to the site of the primary tumor and the disease stage have been presented. All hazard ratios favored treatment with ERBITUX + radiotherapy over radiotherapy alone. However, the study was not powered to detect these sub-group differences. - The 2-year locoregional control rate (ie the number of patients with locoregional control at the specified date) was also markedly higher with ERBITUX plus radiotherapy (50%) than with radiotherapy alone (41%). - Overall, the addition of ERBITUX to radiotherapy led to a 32% reduction in the risk of locoregional failure. 1. Bonner J, Harari P, Giralt J, et al. N Eng J Med 2006;354:567-578
  • - This slide shows the Kaplan-Meier curve for locoregional control for all patients randomly assigned to ERBITUX plus radiotherapy or radiotherapy alone. - The median duration of locoregional control was 14.9 months with radiotherapy alone and 24.4 months with ERBITUX plus radiotherapy (HR 0.68, 95% CI 0.52, 0.89; p=0.005), representing an increase of 9.5 months in favor of ERBITUX. 1. Bonner J, Harari P, Giralt J, et al. N Eng J Med 2006;354:567-578
  • - This slide shows the Kaplan-Meier curve for locoregional control for all patients randomly assigned to ERBITUX plus radiotherapy or radiotherapy alone. - The median duration of locoregional control was 14.9 months with radiotherapy alone and 24.4 months with ERBITUX plus radiotherapy (HR 0.68, 95% CI 0.52, 0.89; p=0.005), representing an increase of 9.5 months in favor of ERBITUX. 1. Bonner J, Harari P, Giralt J, et al. N Eng J Med 2006;354:567-578
  • - Adding ERBITUX to radiotherapy significantly prolonged median overall survival by nearly 20 months (from 29.3 to 49.0 months) compared with radiotherapy (HR 0.74, 95% CI 0.57, 0.97, p=0.03). - There was also an increase in favor of ERBITUX plus radiotherapy in the 3-year (55% versus 45%) survival rates, representing an absolute 3-year survival benefit of 10%. 1. Bonner J, Harari P, Giralt J, et al. N Eng J Med 2006;354:567-578
  • - This slide shows the Kaplan-Meier curve for overall survival for all patients randomly assigned to radiotherapy alone or ERBITUX plus radiotherapy. - The median duration of survival was 29.3 months for radiotherapy alone and 49.0 months for ERBITUX plus radiotherapy (HR 0.74, 95% CI 0.57, 0.97; p=0.03), representing an increase of nearly 20 months in favor of ERBITUX. - Although there are data for only a few patients beyond 5 years of treatment, the curves show that the benefit of ERBITUX plus radiotherapy is prolonged and is maintained for several years after completion of treatment. 1. Bonner J, Harari P, Giralt J, et al. N Eng J Med 2006;354:567-578
  • - The combination of ERBITUX and radiotherapy was well tolerated. Importantly, ERBITUX did not significantly increase the typical acute side effects associated with radiotherapy, such as mucositis, radiation dermatitis and dysphagia. - As expected, there were a number of side effects associated with ERBITUX that were either typical of EGFR inhibitors (skin reactions) or MAbs (infusion-related reactions). - The incidence of grade 3-5 infusion-related reactions with ERBITUX was low (3%). Four patients discontinued treatment with ERBITUX due to such reactions. 1. Bonner J, Harari P, Giralt J, et al. N Eng J Med 2006;354:567-578
  • - A sub-group analysis[1] of the phase III randomized Bonner et al. study[2] (comparing ERBITUX plus radiotherapy with radiotherapy alone in locally advanced SCCHN), assessed whether the addition of ERBITUX to radiotherapy had any impact on organ (larynx) preservation in patients with laryngeal or hypopharyngeal cancer. 1. Bonner J, Harari P, Giralt J, et al. J Clin Oncol 2005;23(16S):Abstract 5533. Updated information presented at ASCO 2. Bonner J, Harari P, Giralt J, et al. N Eng J Med 2006;354:567-578
  • - In terms of treatment, the most commonly used radiotherapy fractionation scheme was concomitant boost radiotherapy (56%), followed by once daily (26%) and twice daily (18%) fractionation. - The addition of ERBITUX to radiotherapy statistically significantly prolonged the median duration of locoregional control by 9.5 months, from 14.9 to 24.4 months (hazard ratio [HR] 0.68, 95% CI 0.52, 0.89; p=0.005). - The effects of treatment on locoregional control according to the site of the primary tumor and the disease stage have been presented. All hazard ratios favored treatment with ERBITUX + radiotherapy over radiotherapy alone. However, the study was not powered to detect these sub-group differences. - The 2-year locoregional control rate (ie the number of patients with locoregional control at the specified date) was also markedly higher with ERBITUX plus radiotherapy (50%) than with radiotherapy alone (41%). - Overall, the addition of ERBITUX to radiotherapy led to a 32% reduction in the risk of locoregional failure. 1. Bonner J, Harari P, Giralt J, et al. N Eng J Med 2006;354:567-578
  • - In this analysis, around 80% of the patients in each arm were male, with a median age of 61 years (radiotherapy only) and 59 years (ERBITUX + radiotherapy). - The primary tumor site was the larynx in nearly two-thirds of patients. - The two treatment groups were well balanced, although the incidence of stage III disease was slightly higher in the ERBITUX + radiotherapy arm (38% compared with 28%). - The median duration of treatment for those patients receiving ERBITUX + radiotherapy was eight weeks and the median number of infusions for patients in this group was also eight. 1. Bonner J, Harari P, Giralt J, et al. J Clin Oncol 2005;23(16S):Abstract 5533. Updated information presented at ASCO
  • - In this sub-group analysis, patients receiving ERBITUX plus radiotherapy had a higher rate of locoregional control compared with those receiving radiotherapy alone: this was seen at both one and two years after treatment. - ERBITUX plus radiotherapy achieved a higher rate of larynx preservation than radiotherapy alone. The 2-year larynx preservation rates were 90% in the ERBITUX plus radiotherapy group versus 80% in the radiotherapy alone group. Corresponding 3-year larynx preservation rates were 87% and 77%, respectively. The hazard ratio for larynx preservation was 0.51 in favor of ERBITUX plus radiotherapy. - Median overall survival for the ERBITUX plus radiotherapy treatment group was 23 months compared with 21 months for the radiotherapy alone treatment group. Two- and 3-year survival rates were also higher for the ERBITUX plus radiotherapy group. - ERBITUX plus radiotherapy was well tolerated and ERBITUX did not increase radiotherapy-associated side effects. 1. Bonner J, Harari P, Giralt J, et al. J Clin Oncol 2005;23(16S):Abstract 5533. Updated information presented at ASCO
  • - In this sub-group analysis, patients receiving ERBITUX plus radiotherapy had a higher rate of locoregional control compared with those receiving radiotherapy alone: this was seen at both one and two years after treatment. - ERBITUX plus radiotherapy achieved a higher rate of larynx preservation than radiotherapy alone. The 2-year larynx preservation rates were 90% in the ERBITUX plus radiotherapy group versus 80% in the radiotherapy alone group. Corresponding 3-year larynx preservation rates were 87% and 77%, respectively. The hazard ratio for larynx preservation was 0.51 in favor of ERBITUX plus radiotherapy. - Median overall survival for the ERBITUX plus radiotherapy treatment group was 23 months compared with 21 months for the radiotherapy alone treatment group. Two- and 3-year survival rates were also higher for the ERBITUX plus radiotherapy group. - ERBITUX plus radiotherapy was well tolerated and ERBITUX did not increase radiotherapy-associated side effects. 1. Bonner J, Harari P, Giralt J, et al. J Clin Oncol 2005;23(16S):Abstract 5533. Updated information presented at ASCO
  • - These results suggest that the addition of ERBITUX to radiotherapy conferred a benefit in terms of larynx preservation in patients with hypopharyngeal and laryngeal cancer compared with radiotherapy alone.[1] - It should be noted that the study was not powered for sub-group analysis, and the confidence interval included 1.0. However, the data on the organ preserving potential of ERBITUX are compelling and are consistent with the observation that the addition of ERBITUX to radiotherapy resulted in locoregional control and survival benefits for the overall group of patients.[2] - The value of ERBITUX in this setting is again underlined by the observation that ERBITUX did not increase the often debilitating side effects associated with radiotherapy. 1. Bonner J, Harari P, Giralt J, et al. J Clin Oncol 2005;23(16S):Abstract 5533 Updated information presented at ASCO 2. Bonner J, Harari P, Giralt J, et al. N Eng J Med 2006;354:567-578

Transcript

  • 1. NACCMA Metanylysis Forest plot P=.003 Survival Functions 1.1 1.0 .9 .8 .7 stgnw .6 3.00 Cum Survival .5 3.00-censored .4 1.00 .3 1.00-censored 0 10 20 30 40 50 60 70 INTERPRETATION OS Kaplan Meier Phase III trial Clinical trials Multivariate analysis Level of evidenceBio-medical statistics Sheh Rawat
  • 2. NACCMA Metanalysis Forest plot P=.003 Survival Functions 1.1 1.0 .9 .8 .7 stgnw .6 3.00 Cum Survival .5 3.00-censored .4 1.00 .3 1.00-censored 0 10 20 30 40 50 60 70 OS Kaplan Meier Phase III trial Clinical trials Multivariate analysis Level of evidenceBio-medical statistics Dr Sheh Rawat
  • 3. NACCMA Metanalysis Forest plot P=.003 Survival Functions 1.1 Primary And secondary end points 1.0 .9 .8 .7 stgnw .6 3.00 Cum Survival .5 3.00-censored .4 1.00 Informed consent .3 1.00-censored 0 10 20 30 40 50 60 70 OS Kaplan Meier Phase III trial Randomisation Clinical trials Multivariate analysis Level of evidenceBio-medical statistics Dr Sheh Rawat
  • 4. NACCMA Metanalysis Forest plot P=.003 Survival Functions 1.1 1.0 DNB:Diplomate in National Board .9 .8 .7 stgnw DNB:Did Not Bat .6 3.00 Cum Survival .5 3.00-censored .4 1.00 .3 1.00-censored 0 10 20 30 40 50 60 70 OS Kaplan Meier Phase III trial Clinical trials Multivariate analysis Level of evidenceBio-medical statistics Dr Sheh Rawat
  • 5. Rising sunGood Morning
  • 6. Or did anyoneof you think itwas sunset?Good Evening!
  • 7. You can prove anything withstatistics. So act with caution in interpreting, and integrity while presenting data
  • 8. An Overview• Clinical trials and Levels of evidence• Definitions and terminology• Collection of data and creating database• How to analyze ?
  • 9. • The need• Types of trials• Levels of evidence• Eligibility criteria• Informed consent• Benefits and possible risks of participating in a clinical trial• Randomisaton/blind/double blind/multicentric• Defining end points (primary and secondary)• Statistical methods• Interim analysis• Publication
  • 10. The need of clinical trials• “Where the value of a treatment, new or old, is doubtful, there may be a higher moral obligation to test it critically than to continue to prescribe it year-in-year-out with the support merely of custom or wishful thinking.” FHK Green
  • 11. Clinical trials are experiments todetermine the value of treatments.• There are two key components to the experimental approach.
  • 12. Clinical trials are experiments todetermine the value of treatments.• There are two key components to the experimental approach.• First, results rather than plausible reasoning are required to support conclusions.
  • 13. Clinical trials are experiments to determine the value of treatments.• There are two key components to the experimental approach.• First, results rather than plausible reasoning are required to support conclusions.• Second, experiments should be prospectively planned and conducted under controlled conditions to provide definitive answers to well- defined questions.
  • 14. Types of Trials• Prevention trials• Screening trials• Diagnostic trials study tests or procedures that could be used to identify cancer• Treatment trials• Quality-of-life (also called supportive care) trials• Genetics studies
  • 15. Who sponsors clinical trials?• The National Cancer Institute (NCI) and other parts of the National Institutes of Health (NIH),• the Department of Defense,• the Department of Veterans Affairs, sponsor and conduct clinical trials
  • 16. What are eligibility criteria, and why are they important?• Each study’s protocol has guidelines for who can or cannot participate in the study. These guidelines, called eligibility criteria, describe characteristics that must be shared by all participants.
  • 17. What are eligibility criteria, and why are they important?• The criteria differ from study to study.• They may include age, gender, medical history, and current health status.• Eligibility criteria for treatment studies often require that patients have a particular type and stage of cancer.
  • 18. ERBITUX + RT in locally advanced SCCHN Patient inclusion criteriaEX • Measurable disease • Pathologically demonstrated SCC of the oropharynx,A hypopharynx, or larynxM • Stage III or IV disease with an expected survival ofP >12 months • Medically able to withstand a course of definitive RTL • Karnofsky PS > 60%E • No evidence of distant metastatic disease Bonner et al. N Eng J Med 2006;354:567-578
  • 19. What are eligibility criteria, and why are they important?Enrolling participants with similarcharacteristics helps to ensure that theresults of the trial will be due to what isunder study and not other factors.
  • 20. What are eligibility criteria, and why are they important?In this way, eligibility criteria helpresearchers achieve accurate andmeaningful results.
  • 21. What are eligibility criteria, and why are they important? These criteria also minimize the risk of a person’s condition becoming worse by participating in the study.
  • 22. What is informed consent?Informed consent is a process bywhich people learn the important factsabout a clinical trial to help themdecide whether to participate.
  • 23. What is informed consent?This information includes details aboutwhat is involved, such as the purposeof the study, the tests and otherprocedures used in the study, and thepossible risks and benefits.
  • 24. What is informed consent?• In addition to talking with the doctor or nurse, people receive a written consent form explaining the study.• People who agree to take part in the study are asked to sign the informed consent form.
  • 25. What is informed consent?However, signing the form does notmean people must stay in the study.People can leave the study at any time—either before the study starts or atany time during the study or the follow-up period.
  • 26. What is informed consent?The informed consent processcontinues throughout the study. If newbenefits, risks, or side effects arediscovered during the study, theresearchers must inform theparticipants. They may be asked tosign new consent forms if they want tostay in the study.
  • 27. Institutional Ethics Committee(IEC)/Institutional ReviewBoard (IRB)
  • 28. ETHICAL REVIEW PROCEEDURESBASIC RESPONSIBILITIES1) To protect the dignity,rights and well being of the potential research participants2) To ensure that universal ethical values and international scientific standards are expressed in terms of local community and customs3) To assist in the development and the education of a research community responsive to local health care requirements
  • 29. COMPOSITION1)Chairperson2) 1-2 Basic Medical Scientists3) 1-2 Clinicians from various institutes4) One Legal expert or retired judge5) One Social scientist/ Representative of non-governmentalvoluntary agency6) One Philosopher /Ethicist7)One lay person from the community8) Member Secretary REVIEW PROCEDURESThe ethical review should be done through formal meetings andshould not resort to decisions through circulation of proposals
  • 30. Where do clinical trials take place? doctors’ officesclinics
  • 31. Where do clinical trials take place? doctors’ officesclinics cancer centers veterans’ and military hospitals community hospitals
  • 32. Where do clinical trials take doctors’ offices place? clinics cancer centers veterans’ and military hospitals community hospitalscities and towns across the countryand in other countries. multicentrc
  • 33. Where do clinical trials take place?EXAMPLE
  • 34. Clinical trials and Levels of evidence• Phase I: To define and to characterize the new treatment to set the basis for later investigations of efficacy and superiority. eg. Establishment of MTD, toxicity profile, anti tumor activity, basic clinical pharmacology and recommendation of doses for phase II studies.• For non life threatening diseases: Conducted on human volunteers,• For life threatening diseases (cancer, HIV): Conducted on patients.
  • 35. ERBITUX + RT in locally advanced SCCHNE Phase I study of anti-epidermal growth factor receptor antibody cetuximab in combinationX with radiation therapy in patients withA advanced head and neck cancerMP Robert F, Ezekiel MP, Spencer SA, Meredith RF, Bonner JA,L Khazaeli MB, Saleh MN, Carey D, LoBuglio AF, Wheeler RH, Cooper MR, Waksal HWERobert et al. J Clin Oncol 2001;19:3234-3243
  • 36. ERBITUX + RT in locallyadvanced SCCHN Study design Previously untreated patients with SCCHN, stage III or IV, or recurrent, not resectable for curative intent n=16EX ERBITUX initial dose (100, 200, 400, orA 500 mg/m2) followed by 7 weekly maintenance doses (100, 200, or 250 mg/m2)M + RT: conventional (70 Gy, 2 Gy / d) orP hyperfractionated (76.8 Gy, 1.2 Gy bid)L Follow until disease progressionERobert et al. J Clin Oncol 2001;19:3234-3243
  • 37. • The dose levels themselves are commonly based on a modified Fibonacci series. The second level is twice the starting dose, the third level is 67% greater than the second, the fourth level is 50% greater than the third, the fifth is 40% greater than the fourth, and each subsequent step is 33% greater than that preceding it.
  • 38. Traditional phase I trials have three limitations:• They sometimes expose too many patients to subtherapeutic doses of the new drug.• The trials may take a long time to complete.• They provide very limited information about interpatient variability and cumulative toxicity.
  • 39. accelerated titration designs -ph I trials contd..• New trial designs have been developed to address these problems.• One new class of designs, accelerated titration designs, permit within-patient dose escalation and use only one patient per dose level until grade 2 or greater toxicity is seen. Doses are titrated within patients to achieve grade 2 toxicity.
  • 40. accelerated titration designs -ph I trials contd..• Accelerated titration designs appear to be effective in reducing the number of patients who are undertreated, speeding the completion of phase I trials, and providing increased information.
  • 41. Clinical trials and Levels of evidence• Phase II: used to screen new regimens for activity and to decide which ones to be tested further. Usually designed with 2 or more stages of accrual, allowing early stopping due to inactivity of the regimen.• Phase III: Randomized trials where the outcome is survival or, time until an adverse event.
  • 42. Clinical trials and Levels of evidence• Phase IV trials are conducted to further evaluate the long-term safety and effectiveness of a treatment.
  • 43. • They usually take place after the treatment has been approved for standard use. Several hundred to several thousand people may take part in a phase IV study.
  • 44. • These studies are less common than phase I, II, or III trials.• People who participate in a clinical trial work with a research team. Team members may include doctors, nurses, social workers, dietitians, and other health professionals. The health care team provides care, monitors participants’ health, and offers specific instructions about the study.
  • 45. What are some of the benefits of taking part in a clinical trial?
  • 46. What are some of the benefits of taking part in a clinical trial?• Participants have access to promising new approaches that are often not available outside the clinical trial setting.• The approach being studied may be more effective than the standard approach.• Participants receive regular and careful medical attention from a research team that includes doctors and other health professionals.
  • 47. What are some of the benefits of taking part in a clinical trial?• Participants may be the first to benefit from the new method under study.• Results from the study may help others in the future.
  • 48. What are some of the possible risksassociated with taking part in a clinical trial?
  • 49. What are some of the possible risksassociated with taking part in a clinical trial? • New drugs or procedures under study are not always better than the standard care to which they are being compared. • New treatments may have side effects or risks that doctors do not expect or that are worse than those resulting from standard care. • Participants in randomized trials will not be able to choose the approach they receive.
  • 50. What are some of the possible risks associated with taking part in a clinical trial?• Health insurance and managed care providers may not cover all patient care costs in a study.• Participants may be required to make more visits to the doctor than they would if they were not in the clinical trial.
  • 51. • The need• Types of trials• Eligibility criteria• Informed consent• Benefits and possible risks of participating in a clinical trial• Levels of evidence• Randomisaton/blind/double blind/multicentric• Defining end points (primary and secondary)• Statistical methods• Interim analysis• Publication
  • 52. Clinical trials and Levels of evidence: ASCO guidelines (JCO;17:1999) • Level 1: Meta-analysis of multiple, well designed, controlled studies. Randomized trials- high powered ( low false+, low false - errors) (Forest plot, L`Abbe plots-odds ratio) • Level II: At least 1 well designed experimental study. Randomized Trials having low power (hg false + and /or false –ve errors)
  • 53. Metaanalysis• A metaanalysis is a quantitative summary of research in a particular area.• It is distinguished from the traditional literature review by its emphasis on quantifying results of individual studies and combining results across studies.
  • 54. Metaanalysis-Contd..• Key components of this approach are:• to include only randomized clinical trials,• to include all relevant randomized clinical trials that have been initiated, regardless of whether they have been published,• to exclude no randomized patients from the analysis, and• to assess therapeutic effectiveness based on the average results pooled across trials
  • 55. Metaanalysis-Contd..• Including all relevant randomized trials that have been initiated in a geographic area (e.g., the world, or the Americas and Europe) represents an attempt to avoid publication bias.• Avoiding exclusion of any randomized patients also functions to avoid bias.• Assessing therapeutic effectiveness based on average pooled results is an attempt to make the evaluation on the totality of evidence rather than on extreme isolated reports.
  • 56. E X A M P L12% benefit in overall survival: E
  • 57. Metanalysis• 1: Cochrane Database Syst Rev. 2004;(2):CD001774. Neoadjuvant chemotherapy for locally advanced cervix E cancer.Neoadjuvant Chemotherapy for Cervical Cancer Meta-Analysis Collaboration (NACCCMA) X• OBJECTIVES: This systematic review and individual patient data (IPD) meta-analysis aimed to assess the A effect of neoadjuvant chemotherapy in two comparisons: (1) neoadjuvant chemotherapy followed by radical M radiotherapy compared to the same radiotherapy NACT-RTP alone; and RT• (2) neoadjuvant chemotherapy followed by surgery AloneL compared to radical radiotherapy alone. NACT-SX E Eur J Cancer. 2003 Nov;39(17):2470-86. RT Alone
  • 58. Metanalysis (NACCCMA) NACT-RT Vs RT Alone• MAIN RESULTS: In the first comparison, we obtained data from 18 trials and 2074 patients. When all trials were considered together, a high level of statistical heterogeneity suggested that the results could not be combined indiscriminately. A substantial amount of heterogeneity was explained by E• separate analyses of groups of trials. Trials using chemotherapy cycle lengths shorter than 14 days (HR = 0.83, X 95% CI = 0.69 to 1.00, p = 0.046) or cisplatin dose intensities greater than 25 mg/m2 per week (HR = 0.91, 95% CI =0.78 to 1.05, p = 0.20) tended to show an advantage for neo adjuvant chemotherapy on survival. A• In contrast, trials using cycle lengths longer than 14 days (HR =1.25, 95% CI = 1.07 to 1.46, p = 0.005) or cisplatin dose intensities lower than25 M mg/m2 per week (HR = 1.35, 95% CI = 1.11 to 1.14, p = 0.002) tended to• show a detrimental effect of neo adjuvant chemotherapy on survival. In the second comparison, data from 5 trials and 872 patients were P obtained. The combined results from all trials (HR = 0.65, 95% CI = 0.53 to 0.80, p = 0.0004) indicate da highly significant reduction in the risk of death with neo adjuvant chemotherapy, but there were some differences between L trials in their design and results. E NACT-Surgery Vs RT Alone
  • 59. Metaanalysis-Contd..• In calculating average treatment effects, a measure of difference in outcome between treatments is calculated separately for each trial. For example, an estimate of the logarithm of the hazard ratio can be computed for each trial. A weighted average of these study-specific differences then is computed, and the statistical significance of this average is evaluated.
  • 60. Impact of Treatment on MortalityE Study name Statistics for each study Odds Lower Upper Odds ratio and 95% CI ratio limit limitX Kelly, 1964 0.590 0.096 3.634 Hedrin, 1980 0.464 0.201 1.074A Leigh, 1962 Novak, 1992 0.394 0.490 0.076 0.088 2.055 2.737M Saint, 1998 1.250 0.479 3.261 Pilbean, 1936 0.129 0.027 0.605 Day, 1960 0.313 0.054 1.805P Kelly, 1966 Singh, 2000 0.429 0.718 0.070 0.237 2.620 2.179 Stewart, 1994 0.143 0.082 0.250L 0.328 0.233 0.462 0.01 0.1 1 10 100E Favours Tx Favours Pbo Meta Analysisthe point estimate is represented by a square.
  • 61. Metaanalysis-Contd..• This approach to metaanalysis requires access to individual patient data for all randomized patients in each trial. It also requires collaboration of the leaders of all the relevant trials and is very labor- intensive. Nevertheless, it represents the gold standard for metaanalysis methodology.
  • 62. Metaanalysis-Contd..• the metaanalysis may be useful for answering important questions about a class of treatments that the individual trials cannot address reliably .
  • 63. Metaanalysis is not analternative to properlydesigned and sizedrandomized clinicaltrials.
  • 64. Clinical trials and Levels of evidence: ASCO guidelines (JCO;17:1999) • Level 1: Meta-analysis of multiple, well designed, controlled studies. Randomized trials- high powered ( low false+, low false - errors) (Forest plot, L`Abbe plots-odds ratio) • Level II: At least 1 well designed experimental study. Randomized Trials having low power (hg false + and /or false –ve errors)
  • 65. Randomisation
  • 66. ERBITUX + RT in locally advanced SCCHN Study design Patients with measurable locally advanced SCCHN (stratified by KPS;node+/0;T1-3/4; RT regimen)E RandomizationXA RT RT as before + once or twice daily or concomitant ERBITUX initial 400 mg/m2 2-hM boost for 7 - 8 weeks infusion then 250 mg/m2 1-h infusion weekly for at least 7 dosesPLE Follow until disease progression or up to 5 years Bonner et al. N Eng J Med 2006;354:567-578
  • 67. ERBITUX + RT for larynx preservation Study design Subgroup analysisE Patients with stage III / IV SCC of larynx and hypopharynx (stratified by KPS;node+/-;T1-3/4; radiation regimen)X n=171A n=78 Randomized n=93M Radiotherapy Radiotherapy as before +P once or twice daily or ERBITUX initial 400 mg/m2 concomitant boost for 6 - 2-h infusion then 250 mg/m2L 7 weeks 1-h infusion weeklyE for at least 7 dosesBonner et al. J Clin Oncol 2005;23(16S):Abstract 5533Updated information presented at ASCO 2005
  • 68. Randomisation-contd..• There is generally differential bias in the selection of patients to be treated resulting from judgments by the physicians, self-selection by the patients, and differences in referral patterns.• There may be bias in treatment ineligibility rates. Current patients sometimes are excluded from analysis for not meeting eligibility criteria, not receiving "adequate" treatment, refusing treatment, or committing a major protocol violation.• The control group, on the other hand, generally contains all the patients.
  • 69. Randomisation-contd..• There may be differences in the distribution of known and unknown prognostic factors between the controls and the current treatment group.• Often, there is inadequate information to determine whether such differences are present, and current known prognostic factors may not have been measured for the controls.
  • 70. Randomisation-contd..• Randomization does not ensure that the study will include a representative sample of all patients with the disease, but it does help to ensure an unbiased evaluation of the relative merits of the two treatments for the types of patients entered.
  • 71. At what point in time is randomisation done?• Randomization of a patient should be performed after the patient has been found eligible and has consented to participate in the trial and to accept either of the randomized options.• A truly random and nondecipherable randomization procedure should be used and implemented by calling a central randomization office staffed by individuals who are independent of participating physicians.
  • 72. Clinical trials and Levels of evidence: ASCO guidelines (JCO;17:1999) • Level 1: Meta-analysis of multiple, well designed, controlled studies. Randomized trials- high powered ( low false+, low false - errors) (Forest plot, L`Abbe plots-odds ratio) • Level II: At least 1 well designed experimental study. Randomized Trials having low power (hg false + and /or false –ve errors)
  • 73. Power of a trial
  • 74. Power of a trial• The probability of obtaining a statistically significant result when the treatments differ in effectiveness is called the power of the trial.• As the sample size and extent of follow-up increases, the power increases.• The power depends critically, however, on the size of the true difference in effectiveness of the two treatments.• Generally, one sizes the trial so that the power is either .80 or .90 when the true difference in effectiveness is the smallest size that is considered medically important to detect.
  • 75. Clinical trials and Levels of evidence: ASCO guidelines (JCO;17:1999) • Level 1: Meta-analysis of multiple, well designed, controlled studies. Randomized trials- high powered ( low false+, low false - errors) (Forest plot, L`Abbe plots-odds ratio) • Level II: At least 1 well designed experimental study. Randomized Trials having low power (hg false + and /or false –ve errors)
  • 76. Forest Plot
  • 77. Forest plot
  • 78. Impact of Treatment on Mortality Study name Statistics for each study Odds ratio and 95% CI Odds Lower Upper ratio limit limit Kelly, 1964 0.590 0.096 3.634 Hedrin, 1980 0.464 0.201 1.074 Leigh, 1962 0.394 0.076 2.055 Novak, 1992 0.490 0.088 2.737 Saint, 1998 1.250 0.479 3.261 Pilbean, 1936 0.129 0.027 0.605 Day, 1960 0.313 0.054 1.805 Kelly, 1966 0.429 0.070 2.620 Singh, 2000 0.718 0.237 2.179 Stewart, 1994 0.143 0.082 0.250 0.328 0.233 0.462 0.01 0.1 1 10 100 Favours Tx Favours Pbothe confidence interval (CI) for each Meta Analysisstudy is represented by a horizontal line
  • 79. Impact of Treatment on Mortality Study name Statistics for each study Odds ratio and 95% CI Odds Lower Upper ratio limit limit Kelly, 1964 0.590 0.096 3.634 Hedrin, 1980 0.464 0.201 1.074 Leigh, 1962 0.394 0.076 2.055 Novak, 1992 0.490 0.088 2.737 Saint, 1998 1.250 0.479 3.261 Pilbean, 1936 0.129 0.027 0.605 Day, 1960 0.313 0.054 1.805 Kelly, 1966 0.429 0.070 2.620 Singh, 2000 0.718 0.237 2.179 Stewart, 1994 0.143 0.082 0.250 0.328 0.233 0.462 0.01 0.1 1 10 100 Favours Tx Favours Pbo Meta Analysisthe point estimate is represented by a square.
  • 80. Impact of Treatment on Mortality Study name Statistics for each study Odds ratio and 95% CI Odds Lower Upper ratio limit limit Kelly, 1964 0.590 0.096 3.634 Hedrin, 1980 0.464 0.201 1.074 Leigh, 1962 0.394 0.076 2.055 Novak, 1992 0.490 0.088 2.737 Saint, 1998 1.250 0.479 3.261 Pilbean, 1936 0.129 0.027 0.605 Day, 1960 0.313 0.054 1.805 Kelly, 1966 0.429 0.070 2.620 Singh, 2000 0.718 0.237 2.179 Stewart, 1994 0.143 0.082 0.250 0.328 0.233 0.462 0.01 0.1 1 10 100 Favours Tx Favours Pbo Meta AnalysisThe size of the square corresponds to the weight of the study inthe meta-analysis. ; this is the Mantel-Haenszel weight.
  • 81. The confidence interval fortotals are represented by adiamond shape. The pooledestimate is marked with an unfilled diamond thathas an ascending dotted line from its upperpoint. Confidence intervals of pooled estimatesare displayed as a horizontal line through thediamond; this line might be contained within thediamond if the confidence interval is narrow.
  • 82. The confidence interval fortotals are represented by adiamond shape. The pooledestimate is marked with an unfilled diamond thathas an ascending dotted line from its upperpoint. Confidence intervals of pooled estimatesare displayed as a horizontal line through thediamond; this line might be contained within thediamond if the confidence interval is narrow.
  • 83. The confidence interval fortotals are represented by adiamond shape. The pooledestimate is marked with an unfilled diamond thathas an ascending dotted line from its upperpoint. Confidence intervals of pooled estimatesare displayed as a horizontal line through thediamond; this line might be contained within thediamond if the confidence interval is narrow.
  • 84. • The graph is a forest plot where the confidence interval (CI) for each study is represented by a horizontal line and the point estimate is represented by a square. The size of the square corresponds to the weight of the study in the meta-analysis. The confidence interval for totals are represented by a diamond shape. The scale used on the graph depends on the statistical method. Dichotomous data (except for risk differences) are displayed on a logarithmic scale. Continuous data and risk differences are displayed on a linear scale.
  • 85. How to interpret the Forest plot?
  • 86. OR = Intervention group Intervention group 1.0 does does (no better than control worse than control effecti. Probably a small study, with a wide confidence interval, crossing the line of noeffect (OR = 1). Unable to say if the intervention worksii. Probably a small study, wide confidence interval , but does not cross OR = 1;suggests intervention works but weak evidenceiii. Larger study, narrow confidence interval: but crosses OR = 1; no evidencethat intervention worksiv. Large study, narrow confidence intervals: entirely to left of OR = 1; suggestsintervention worksv. Small study, wide confidence intervals, suggests intervention is detrimentalvi. Meta-analysis of all identified studies: suggests intervention works.
  • 87. OR = Intervention group Intervention group 1.0 does does (no better than control worse than control effecti. Probably a small study, with a wide confidence interval, crossing the line of noeffect (OR = 1). Unable to say if the intervention worksii. Probably a small study, wide confidence interval , but does not cross OR = 1;suggests intervention works but weak evidenceiii. Larger study, narrow confidence interval: but crosses OR = 1; no evidencethat intervention worksiv. Large study, narrow confidence intervals: entirely to left of OR = 1; suggestsintervention worksv. Small study, wide confidence intervals, suggests intervention is detrimentalvi. Meta-analysis of all identified studies: suggests intervention works.
  • 88. OR = Intervention group Intervention group 1.0 does does (no better than control worse than control effecti. Probably a small study, with a wide confidence interval, crossing the line of noeffect (OR = 1). Unable to say if the intervention worksii. Probably a small study, wide confidence interval , but does not cross OR = 1;suggests intervention works but weak evidenceiii. Larger study, narrow confidence interval: but crosses OR = 1; no evidencethat intervention worksiv. Large study, narrow confidence intervals: entirely to left of OR = 1; suggestsintervention worksv. Small study, wide confidence intervals, suggests intervention is detrimentalvi. Meta-analysis of all identified studies: suggests intervention works.
  • 89. OR = Intervention group Intervention group 1.0 does does (no better than control worse than control effecti. Probably a small study, with a wide confidence interval, crossing the line of noeffect (OR = 1). Unable to say if the intervention worksii. Probably a small study, wide confidence interval , but does not cross OR = 1;suggests intervention works but weak evidenceiii. Larger study, narrow confidence interval: but crosses OR = 1; no evidencethat intervention worksiv. Large study, narrow confidence intervals: entirely to left of OR = 1; suggestsintervention worksv. Small study, wide confidence intervals, suggests intervention is detrimentalvi. Meta-analysis of all identified studies: suggests intervention works.
  • 90. OR = Intervention group Intervention group 1.0 does does (no better than control worse than control effecti. Probably a small study, with a wide confidence interval, crossing the line of noeffect (OR = 1). Unable to say if the intervention worksii. Probably a small study, wide confidence interval , but does not cross OR = 1;suggests intervention works but weak evidenceiii. Larger study, narrow confidence interval: but crosses OR = 1; no evidencethat intervention worksiv. Large study, narrow confidence intervals: entirely to left of OR = 1; suggestsintervention worksv. Small study, wide confidence intervals, suggests intervention is detrimentalvi. Meta-analysis of all identified studies: suggests intervention works.
  • 91. OR = Intervention group Intervention group 1.0 does does (no better than control worse than control effecti. Probably a small study, with a wide confidence interval, crossing the line of noeffect (OR = 1). Unable to say if the intervention worksii. Probably a small study, wide confidence interval , but does not cross OR = 1;suggests intervention works but weak evidenceiii. Larger study, narrow confidence interval: but crosses OR = 1; no evidencethat intervention worksiv. Large study, narrow confidence intervals: entirely to left of OR = 1; suggestsintervention worksv. Small study, wide confidence intervals, suggests intervention is detrimentalvi. Meta-analysis of all identified studies: suggests intervention works.
  • 92. OR = Intervention group Intervention group 1.0 does does (no better than control worse than control effecti. Probably a small study, with a wide confidence interval, crossing the line of noeffect (OR = 1). Unable to say if the intervention worksii. Probably a small study, wide confidence interval , but does not cross OR = 1;suggests intervention works but weak evidenceiii. Larger study, narrow confidence interval: but crosses OR = 1; no evidencethat intervention worksiv. Large study, narrow confidence intervals: entirely to left of OR = 1; suggestsintervention worksv. Small study, wide confidence intervals, suggests intervention is detrimentalvi. Meta-analysis of all identified studies: suggests intervention works.
  • 93. OR = Intervention group Intervention group 1.0 does does (no better than control worse than control effecti. Probably a small study, with a wide confidence interval, crossing the line of noeffect (OR = 1). Unable to say if the intervention worksii. Probably a small study, wide confidence interval , but does not cross OR = 1;suggests intervention works but weak evidenceiii. Larger study, narrow confidence interval: but crosses OR = 1; no evidencethat intervention worksiv. Large study, narrow confidence intervals: entirely to left of OR = 1; suggestsintervention worksv. Small study, wide confidence intervals, suggests intervention is detrimentalvi. Meta-analysis of all identified studies: suggests intervention works.
  • 94. OR = Intervention group Intervention group 1.0 does does (no better than control worse than control effecti. Probably a small study, with a wide confidence interval, crossing the line of noeffect (OR = 1). Unable to say if the intervention worksii. Probably a small study, wide confidence interval , but does not cross OR = 1;suggests intervention works but weak evidenceiii. Larger study, narrow confidence interval: but crosses OR = 1; no evidencethat intervention worksiv. Large study, narrow confidence intervals: entirely to left of OR = 1; suggestsintervention worksv. Small study, wide confidence intervals, suggests intervention is detrimentalvi. Meta-analysis of all identified studies: suggests intervention works.
  • 95. OR = Intervention group Intervention group 1.0 does does (no better than control worse than control effecti. Probably a small study, with a wide confidence interval, crossing the line of noeffect (OR = 1). Unable to say if the intervention worksii. Probably a small study, wide confidence interval , but does not cross OR = 1;suggests intervention works but weak evidenceiii. Larger study, narrow confidence interval: but crosses OR = 1; no evidencethat intervention worksiv. Large study, narrow confidence intervals: entirely to left of OR = 1; suggestsintervention worksv. Small study, wide confidence intervals, suggests intervention is detrimentalvi. Meta-analysis of all identified studies: suggests intervention works.
  • 96. OR = Intervention group Intervention group 1.0 does does (no better than control worse than control effecti. Probably a small study, with a wide confidence interval, crossing the line of noeffect (OR = 1). Unable to say if the intervention worksii. Probably a small study, wide confidence interval , but does not cross OR = 1;suggests intervention works but weak evidenceiii. Larger study, narrow confidence interval: but crosses OR = 1; no evidencethat intervention worksiv. Large study, narrow confidence intervals: entirely to left of OR = 1; suggestsintervention worksv. Small study, wide confidence intervals, suggests intervention is detrimentalvi. Meta-analysis of all identified studies: suggests intervention works.
  • 97. Clinical trials and Levels of evidence ASCO guidelines (JCO;17:1999)• Level III: Well designed, quasi-experimental studies such as non randomized, controlled, single group. Pre-post, cohort, time or matched case control series.• Level IV: Well designed non experimental studies.• Level V: Case reports and clinical examples.
  • 98. What level of evidence is “In my experience” ?
  • 99. Hard evidence
  • 100. Evidence basedmedicine
  • 101. • The need• Types of trials• Levels of evidence• Eligibility criteria• Informed consent• Benefits and possible risks of participating in a clinical trial• Randomisaton/blind/double blind/multicentric• Defining end points (primary and secondary)• Statistical methods• Interim analysis• Publication
  • 102. ERBITUX + RT in locally advanced SCCHN Study endpoints Primary endpoint – locoregional control (absence of locoregional disease progression at scheduled follow-up visits) – Secondary endpoints – overall survival – progression-free survival – Safety (Mucositis, Dysphagia, Radiation dermatitis, Weight-loss, Asthenia, Xerostomia, Acne-like rash,Infusion reaction)Bonner et al. N Eng J Med 2006;354:567-578
  • 103. ERBITUX + RT in locally advanced SCCHN Patient and disease characteristics RT only ERBITUX + RT Characteristics % (n=213) % (n=211) Gender: M / F 79 / 21 81 / 19 Median age 58 years 56 years Karnofsky PS: 60 - 80% / 90 - 33 / 66 30 / 70 100% Primary tumor site: Oropharynx 63 56 Hypopharynx 13 17 Larynx 24 27 AJCC stage: III/IV 24 / 76 26 / 74 Tumor stage: T1-3 / 69 / 31 70 / 29 T4 Node stage: N0 / N+ 18 / 82 20 / 80Bonner et al. N Eng J Med 2006;354:567-578
  • 104. ERBITUX + RT improves locoregional control over RT alone in locally advanced SCCHN (1) ERBITUX + P value/ RT only Efficacy RT *Hazard % (n= 213) ratio % (n= 211) Median locoregional 14.9 24.4 0.005 control (months) By site of primary tumor (months): Oropharynx 23.0 49.0 0.61* Larynx 11.9 12.9 0.69* Hypopharynx 10.3 12.5 0.92* By disease stage Stage III 16.2 38.9 0.69* Stage IV 13.5 20.9 0.73* Locoregional control rate 2-year 41 50Bonner et al. N Eng J Med 2006;354:567-578
  • 105. ERBITUX + RT improves locoregional control over RT alone in locally advanced SCCHN (2)Bonner et al. N Eng J Med2006;354:567-578
  • 106. ERBITUX + RT improves locoregional control over RT alone in locally advanced SCCHN (2) Primary End pointBonner et al. N Eng J Med2006;354:567-578
  • 107. ERBITUX + RT prolongs survival over RT alone in locally advanced SCCHN (1) Efficacy RT only ERBITUX P value % + RT (n= 213) % (n= 211) Median follow- 54 months 54 months up Median overall 29.3 49 months 0.03 survival months Three-year 45 55 0.05 survivalBonner et al. N Eng J Med 2006;354:567-578
  • 108. ERBITUX + RT prolongs survival over RT alone in locally advanced SCCHN (2) Secondary end pointBonner et al. N Eng J Med 2006;354:567-578
  • 109. ERBITUX does not increase acute RT-induced toxicity in locally advanced SCCHN Yet another Secondary end point Selected or RT only ERBITUX + relevant grade 3-5 % RT adverse events (n=212) % (n=208) reported Mucositis 52 56 Dysphagia 30 26 Radiation 18 23 dermatitis Weight loss 7 11 Asthenia 5 4 Xerostomia 3 5 Acne-like rash 1 17 Bonner et al. N Eng J Med 2006;354:567-578 Infusion reaction - 3
  • 110. ERBITUX + RT for larynx preservation Improved preservation of larynx with the addition of cetuximab to radiation for cancers of the larynx and hypopharynx Bonner J, Harari P, Giralt J, Baselga J, Shin DM, Cohen R, Jassem J, Azarnia N, Molloy P, Ang K Subgroup analysis of study by Bonner et al. J Clin Oncol 2004;22(14S):Abstract 5507Bonner et al. J Clin Oncol 2005;23(16S):Abstract 5533Updated information presented at ASCO 2005
  • 111. ERBITUX + RT improves locoregional control over RT alone in locally advanced SCCHN (1) ERBITUX + P value/ RT only Efficacy RT *Hazard % (n= 213) ratio % (n= 211) Median locoregional 14.9 24.4 0.005 control (months) By site of primary tumor (months): Oropharynx 23.0 49.0 0.61* Larynx 11.9 12.9 0.69* Hypopharynx 10.3 12.5 0.92* By disease stage Stage III 16.2 38.9 0.69* Stage IV 13.5 20.9 0.73* Locoregional control rate 2-year 41 50Bonner et al. N Eng J Med 2006;354:567-578
  • 112. ERBITUX + RT for larynx preservation Patient characteristics Patient characteristics RT only ERBITUX+RT % (n=78) % (n=93) Median age (years) 61 59 Gender: M / F 79 / 21 80 / 20 Primary tumor site Hypopharynx 35 39 Larynx 65 61 AJCC stage III / IV 28 / 72 38 / 62 ERBITUX treatment (n=91) Median duration of treatment 8 (weeks) Median number of infusions 8Bonner et al. J Clin Oncol 2005;23(16S):Abstract 5533 Updated information presented at ASCO 2005
  • 113. ERBITUX + RT improves the rate of larynx preservation compared with RT Efficacy RT only ERBITUX+RT % (n=78) % (n=93) Locoregional control: Median (months) 12 16 One-year 49 60 Two-year 34 44 S Overall survival: i Median (months) 21 23 m Two-year survival 48 50 i Three-year survival 39 43 Laryngeal preservation: l Two-year 80 a 90Bonner et al. J Clin Oncol 2005;23(16S):Abstract 5533 87 Three-year 77 r Updated information presented at ASCO2005
  • 114. ERBITUX + RT improves the rate of larynx preservation compared with RT Efficacy RT only ERBITUX+RT % (n=78) % (n=93) Locoregional control: Median (months) 12 16 One-year 49 60 Two-year 34 44 Overall survival: Median (months) 21 23 Two-year survival 48 50 Three-year survival 39 43 Laryngeal preservation: Two-year 80 90Bonner et al. J Clin Oncol 2005;23(16S):Abstract 5533 87 Three-year 77 Updated information presented at ASCO2005
  • 115. ERBITUX + RT for larynx preservation Conclusions • The combination of ERBITUX and RT improves laryngeal preservation in patients with laryngeal or hypopharyngeal carcinomas compared with RT aloneBonner et al. J Clin Oncol 2005;23(16S):Abstract 5533Updated information presented at ASCO 2005
  • 116. • The need• Types of trials• Levels of evidence• Eligibility criteria• Informed consent• Benefits and possible risks of participating in a clinical trial• Randomisaton/blind/double blind/multicentric• Defining end points (primary and secondary)• Statistical methods• Interim analysis• Publication
  • 117. Definitions• Mean, mode, median• Statistical significance (P value)• Variance, SD, SE and• Confidence Interval• Age-Adjusted Rate• DFS, OS, Event, Censored cases• Kaplan Meier/Life table methods• Cox Regression• Odds ratio (Forest and L`Abbe plots)
  • 118. Definitions and terminology• A discipline concerned with treatment of numerical data derived from groups of individuals• To summarize our experience so that we and other people can understand its essential features.• To use summary to make estimates or predictions about what is likely to be the case in other (perhaps future) situations.
  • 119. Definitions and terminology• Descriptive : are methods used to summarize or describe our observations.• Inferential: Use of observations as a basis for making estimates or predictions (going beyond the fact).
  • 120. Definitions and terminology Mean, mode, median• Mean: The sum of all the observations divided by no. of observations. 5,10,15,15,20,25,100,150,1000. Mean:• Median: of a series of observations is the value of the central or middle observation when all other observations are listed in order from lowest to highest. 5,10,15,15,20,25,100,150,1000 Median:• Mode: Most frequently occurring value in the series. 5,10,15,15,20,25,100,150,1000• Mode:
  • 121. Definitions and terminology Mean, mode, median• Mean: The sum of all the observations divided by no. of observations. 5,10,15,15,20,25,100,150,1000. Mean:148.5• Median: of a series of observations is the value of the central or middle observation when all other observations are listed in order from lowest to highest. 5,10,15,15,20,25,100,150,1000 Median: 20• Mode: Most frequently occurring value in the series. 5,10,15,15,20,25,100,150,1000• Mode:15
  • 122. Definitions and terminology: Statistical significance• If 2 means differ to more than twice the value of SE of the difference, it is said to be statistically significant i.e. more than is likely to have arisen by chance (1 in 20=.05).• An understanding of statistical significance (p value ) requires understanding of terms like Variance, Standard deviation, Std error.
  • 123. Definitions• Mean, mode, median• Statistical significance (P value)• Variance, SD, SE and• Confidence Interval• Age-Adjusted Rate• DFS, OS, Event, Censored cases• Kaplan Meier/Life table methods• Cox Regression
  • 124. A crow was sitting on a tree, doing nothing all day. A small rabbit saw the crow, and asked him, "Can I also sit like you and do nothing all day long?” The crow answered: "Sure, why not.” So, the rabbit sat on the ground below the crow, and rested. All of a sudden, a fox appeared, Jumped on the rabbit... and ate it.
  • 125. Moral of the story is….To be sitting and doing nothingyou must be sitting very, very high up.
  • 126. Definitions and terminology Variance, SD, SE and P value20 observations of Deviation of each Square of each DeviationSystolic BP in men observation from the from the mean mean (128)98 -30 900160 +32 1024136 +8 64128 0 0130 +2 4114 -14 196123 -5 25134 +6 36128 0 0107 -21 441123 -5 25
  • 127. Definitions and terminology Variance, SD, SE and P value20 observations of Deviation of each Square of each DeviationSystolic BP in men observation from the from the mean mean (128)125 -3 9129 +1 1132 +4 16154 +26 676115 -13 169126 -2 4132 +4 16136 +8 64130 +2 4Sum 2560 0 3674 Mean Sq deviation= 3674/20=183.7
  • 128. Definitions and terminology Variance, SD, SE and P value• Variance= mean squared deviation=183.7 Total no. 20 -1 (n-1)i.e.19=193.4• Std. Deviation=Sq root of variance=13.91• A large standard deviation means frequency distribution is widely spread out from the mean.
  • 129. Definitions and terminology Variance, SD, SE and P value• What is the Utility of Std Deviation? It enables us to test whether the observed diff. between 2 such means are more than would be likely to have arisen by chance.
  • 130. Definitions and terminology Variance, SD, SE and P value• Std. Error: of any statistical value is a measure of the SD that that value would show in taking repeated samples from the same universe of observations. It shows how much variation might be expected to occur merely by chance. Std. Error of diff. between 2 means=• (S.D.1)2 + (S.D.2)2• n1 n2
  • 131. Definitions and terminology Variance, SD, SE and P value• Statistical significance: If 2 means differ to more than twice the value of SE of the difference, it is said to be statistically significant i.e more than is likely to have arisen by chance (1 in 20=.05).• This calculation sets a standard of judgment which is constant from one person to another.
  • 132. Definitions and terminology Variance, SD, SE and P value• A “ significant” answer does not prove that the difference is real; “chance” is still a possible explanation (though unlikely).• A “ not significant” answer does not tell us that Group A does not differ from group B. It tells that “chance” may easily be a reason for that difference.
  • 133. Definitions and terminology Variance, SD, SE and P value• “ p value” does not give the reason for significance or non significance.• It is only by planning and foresight which can ensure comparable groups of patients and only in such circumstances can we infer that the significant difference between groups is more likely to be due to the specific treatment than to any other factor.
  • 134. Confidence Interval• A range of values that has a specified probability of containing the estimated rate or trend of interest.• The 95% (p-value = 0.05) and 99% (p-value = 0.01) confidence intervals are the most commonly used.• If an estimated annual percentage change (APC) is -2.44 with a 95% confidence interval of (-2.83, -2.05), then we are 95% confident that the actual APC is between a decrease of -2.83% and a decrease of 2.05%. Inversely, there is still a 5% chance that the actual APC is not in the confidence interval (between the upper and lower confidence limits)
  • 135. • Confidence intervals are generally much more informative than are significance levels. A confidence interval for the size of the treatment difference provides a range of effects consistent with the data. The significance level tells nothing about the size of the treatment effect because it depends on the sample size. However, it is the size of the treatment effect, as communicated by a confidence interval, that should be used in weighing the costs and benefits of clinical decision making.
  • 136. Definitions and terminology survivals• Disease free survival (DFS,PFS).• Overall Survival (OS): calculated from date of registration or start of treatment.• Cause specific survivals.• Systems available: BMDP,SAS,SPSS• Methods: Life table, Kaplan Meier, Cox regression.
  • 137. “Event” Vital status• DFS• Recurrence, lost to f/up with disease• OS• Death, lost to F/up with disease, status unknown (worst case scenario),etc.
  • 138. Vital status• Alive;tumor free;no recurrence• Alive;tumor free;after recurrence• Alive with persistent, recurrent, or metastatic disease• Alive with primary tumor• Dead;tumor free• Dead with cancer• Unknown;lost to follow up• Completeness of follow up is crucial in any study of survival time to exclude bias in data
  • 139. Definitions and terminology survivals• Disease free survival (DFS,PFS).• Overall Survival (OS): calculated from date of registration or start of treatment.• Cause specific survivals.• Systems available: BMDP,SAS,SPSS• Methods: Life table, Kaplan Meier, Cox regression.
  • 140. Kaplan Meier curve Survival Functions 1.1 1.0 .9 .8 .7 stgnw .6 3.00Cum Survival .5 3.00-censored .4 1.00 .3 1.00-censored 0 10 20 30 40 50 60 70 OS
  • 141. Kaplan Meier curve Survival Functions 1.1 1.0 .9 .8 Life table method .7 stgnw .6 3.00Cum Survival .5 3.00-censored .4 1.00 .3 1.00-censored 0 10 20 30 40 50 60 70 OS
  • 142. Kaplan Meier curve Survival Functions 1.1 1.0 .9 .8 .7 stgnw .6 3.00Cum Survival .5 3.00-censored .4 1.00 .3 1.00-censored 0 10 20 30 40 50 60 70 OS
  • 143. Kaplan Meier method• This kind of data usually includes some censored cases. Censored cases are cases for which the second event isn’t recorded (for example, people still alive disease free at the end of the study).
  • 144. Kaplan Meier method• The Kaplan-Meier procedure is a method of estimating time-to-event models in the presence of censored cases.• It is based on estimating conditional probabilities at each time point when an event occurs and taking the product limit of those probabilities to estimate the survival rate at each point in time.
  • 145. • Censored cases can happen for several reasons:
  • 146. • Censored cases can happen for several reasons:1.for some cases, the event simply doesn’t occur before the end of the study;
  • 147. • Censored cases can happen for several reasons:1.for some cases, the event simply doesn’t occur before the end of the study;2.for other cases, we lose track of their status sometime before the end of the study;
  • 148. • Censored cases can happen for several reasons:1.for some cases, the event simply doesn’t occur before the end of the study;2.for other cases, we lose track of their status sometime before the end of the study;3.still other cases may be unable to continue for reasons unrelated to the study
  • 149. • Censored cases can happen for several reasons:1.for some cases, the event simply doesn’t occur before the end of the study;2.for other cases, we lose track of their status sometime before the end of the study;3.still other cases may be unable to continue for reasons unrelated to the study Collectively, such cases are known as censored cases, and they make this kind of study inappropriate for traditional techniques such as t tests or linear regression.
  • 150. A wife is a wife,No matter, who the hell you are!!
  • 151. Cox Regression• Like Life Tables and Kaplan-Meier survival analysis, Cox Regression is a method for modeling time-to-event data in the presence of censored cases.• However, Cox Regression allows you to include predictor variables (covariates) in your models, allowing you to assess the impact of multiple covariates in the same model.
  • 152. Intention-to-Treat Analysis• One of the important principles in the analysis of phase III trials is called the intention-to-treat principle.• This indicates that all randomized patients should be included in the primary analysis of the trial. For cancer trials, this has often been interpreted to mean all "eligible" randomized patients. Because eligibility requirements sometimes are vague and unverifiable by an external auditor, excluding "ineligible" patients can itself result in bias.
  • 153. Intention-to-Treat Analysis-contd..• However, excluding patients from analysis because of treatment deviations, early death, or patient withdrawal can severely distort the results.• Often, excluded patients have poorer outcomes than do those who are not excluded.• Investigators frequently rationalize that the poor outcome experienced by a patient was due to lack of compliance to treatment, but the direction of causality may be the reverse.
  • 154. Intention-to-Treat Analysis – contd..• In randomized trials, there may be poorer compliance in one treatment group than the other, or the reasons for poor compliance may differ.• Excluding patients, or analyzing them separately (which is equivalent to excluding them), for reasons other than eligibility is generally considered unacceptable.• The intention-to-treat analysis with all eligible randomized patients should be the primary analysis.
  • 155. Intention-to-Treat Analysis – contd..• If the conclusions of a study depend on exclusions, then these conclusions are suspect.• The treatment plan should be viewed as a policy to be evaluated.• The treatment intended cannot be delivered uniformly to all patients, but all eligible patients should generally be evaluable in phase III trials.
  • 156. • The need• Types of trials• Levels of evidence• Eligibility criteria• Informed consent• Benefits and possible risks of participating in a clinical trial• Randomisaton/blind/double blind/multicentric• Defining end points (primary and secondary)• Statistical methods• Interim analysis• Publication
  • 157. Interim analysis• It has become standard in multicenter clinical trials to have a data-monitoring committee review interim results, rather than having the monitoring done by participating physicians.• This approach helps to protect patients by having interim results carefully evaluated by an experienced group of individuals and helps to protect the study from damage that ensues from misinterpretation of interim results.
  • 158. Interim analysis-contd..• Generally, interim outcome information is available to only the data-monitoring committee.• The study leaders are not part of the data- monitoring committee, because they may have a perceived conflict of interest in continuing the trial.• The data-monitoring committee determines when results are mature and should be released.• These procedures are used only for phase III trials.
  • 159. • The need• Types of trials• Levels of evidence• Eligibility criteria• Informed consent• Benefits and possible risks of participating in a clinical trial• Randomisaton/blind/double blind/multicentric• Defining end points (primary and secondary)• Statistical methods• Interim analysis• Publication
  • 160. What happens when a clinical trial is over?• the researchers look carefully at the data before making decisions about the meaning of the findings and further testing.• After a phase I or II trial, the researchers decide whether to move on to the next phase, or stop testing the agent or intervention because it was not safe or effective.
  • 161. What happens when a clinical trial is over? The results of clinical trials are often published in peer-reviewed, scientific journals.
  • 162. What happens when a clinical trial is over?• Peer review is a process by which experts review the report before it is published to make sure the analysis and conclusions are sound.• If the results are particularly important, they may be featured by the media and discussed at scientific meetings before they are published.• Once a new approach has been proven safe and effective in a clinical trial, it may become standard practice.
  • 163. Publication bias• An additional factor to consider is that of publication bias, which denotes the preference of journals to publish positive rather than negative results. A negative result may not be published at all, particularly from a small trial. If it is published, it is likely to appear in a less widely read journal than it would if the result were positive.
  • 164. DeadOrAlive
  • 165. • Publication bias These observations emphasize that results in the medical literature often cannot be accepted at face value.
  • 166. Publication bias• It is essential to recognize that "positive" results need confirmation, particularly positive results of small studies, before they can be believed and applied to the general population.
  • 167. Where can people find moreinformation about clinical trials?• People also have the option of searching for clinical trials on their own. The clinical trials page of the NCIs Web site, located at http://www.cancer.gov/clinicaltrials/ on the Internet,• Another resource is the NIHs ClinicalTrials.gov Web site. ClinicalTrials.gov lists clinical trials sponsored by the NIH, other Federal agencies, and the pharmaceutical industry for a wide range of diseases, including cancer and other conditions. This site can be found at http://clinicaltrials.gov/ on the Internet.
  • 168. ThankyouThis happens only in india
  • 169. How to tabulate & collect in what form?• Strings Status DFS 1:Residual (Names) 2:LFU with disease 3:LFU without disease• Numericals 4 :disease Free (Sex, types of protocols, Status OS stage, race,etc.) 1:Dead due to disease 2:LFU with disease 3:LFU without disease 4:Alive with disease 5:Alive disease free 6:dead other cause
  • 170. Hands on SPSS• Understanding variables.• Entering the data.• Analysis of data.
  • 171. Conclusion • It is a means of coming to conclusions in the face of uncertainty “Act with caution”You can prove anything with statistics.
  • 172. There are lies, dammed lies, and statistics.Figures don’t lie, but liars use figures. Act with Integrity.
  • 173. A little bird was flying south for the winter. It was so cold, the bird froze and fell to the ground in a large field. While it was lying there, a cow came by and dropped some dung on it. As the frozen bird lay there in the pile of cow dung, it began to realise how warm it was. The dung was actually thawing him out!PURR.... He lay there all warm and happy, and soon began to sing for joy. A passing cat heard the bird singing and came to investigate. Following the sound, the cat discovered the bird under the pile of cow dung, and promptly dug him out and ate him!
  • 174. The morals of this story are:1) Not everyone who drops shit onyou is your enemy.2) Not everyone who gets you out ofshit is your friend.3) And when youre in deep shit,keep your mouth shut
  • 175. Don’t ask me 2oo many ?s. I’m not a statistician Thank you. Have a nice day