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ECHOES
IASCT Echoes
IASCT Newsletter - For Private Circulation only
INSIDE THIS ISSUE
President's Note 2-3
Conference Agenda 4
Biosketches and Abstracts 6-21
Greetings From PhUSE 22
Make Life Easy With X And Pipe 24-27
Adaptive Allocation Rules in Clinical Trials 29-31
Summary of Previous IASCT Events 33
Indian Association forStatistics in Clinical Trials
Volume 2, Issue 2December 2010
www.iasct.net
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ECHOES
President’s Note
Dear Friends,
I am pleased to present to you all the special edition of IASCT Newsletter “ECHOES”. This edition of Echoes is special as it features a variety of articles that would interest a wide cross-section of members and gives a brief introduction to the IASCT annual conference.
Clinical research in India is just coming out of its infancy. India, with its new patent regime and well qualified clinical researchers is well on its way of playing a significant role in the global future of clinical research. While we continue to strive for excellence in conducting clinical research which is respected and noticed globally, we cannot forget some basic tenets of doing good clinical research.
In my opinion, good clinical research is based on the following three principles: - (1) Ethics; (2) Transparency; (3) Unbiased Science. Since clinical research involves human beings, ethics is an absolute necessity. Transparency alludes to reporting everything related to clinical research truthfully and factually. Unbiased science is related to doing clinical research which is free of personal biases and uses the latest and most up-to-date scientific methods.
Statistical ideas play a role in each of the above mentioned principles. Design and conduct of clinical trials which include setting clear objectives and hypotheses, appropriate sample size justifications, pre-determined methodology to collect, analyze and present data, clear presentation of data and dispassionate interpretation of results play a role in ethical, transparent and scientifically unbiased clinical research.
As a complement to statistical activities, statistical programming, medical writing and communication and data management activities are equally important. Clear flow of information between writers, programmers, data managers and statisticians is key to doing impactful clinical research. Trained professionals for all these activities become an essential ingredient for what we hope would be a successful recipe for impactful clinical research.
The Indian Association for Statistics in Clinical Trials (www.IASCT.net) was setup as an organization to raise awareness about statistics and the role it can play in doing good clinical research and subsequently to provide training related to statistics and clinical research. We formed this organization more than 2 years ago and at this stage have close to 250 members from all over India. We have conducted 15 workshops in Bangalore, Mumbai and Hyderabad in the past. The topics have ranged from statistical programming using SAS, CDISC standards to advanced Bayesian methodology and survival analyses techniques. Participants (more than 1000) from diverse fields like programming, data management and medical sciences have attended and benefitted from these workshops. A workshop on safety reporting of adverse events combined presentations from statisticians, medical doctors, programmers and pharmacovigilance experts. This co-existence and development of expertise across functional areas was something that IASCT aimed at and has been successful in achieving. All presentations done at the workshops are available on the IASCT website.
We have also tied up with other organizations to provide additional benefits to our members. IASCT members get discounted rates for various programs conducted by the Indian Society for Clinical Research (www.ISCR.org). ISCR is conducting its annual conference in Gurgaon on February 11-12 and IASCT members can enjoy the benefits. We also have a tie up with Pharmaceutical Users Software Exchange (www.PhUSE.eu) group. We have a write-up about PhUSE in this newsletter sent by Steve Bamford who is the president of the society. Please visit the website and see all the benefits that PhUSE users have. IASCT members get special benefits and you can enquire about this by writing to our membership committee.
Finally, I would like to welcome all of you to this 2011- 3-day Annual Conference of IASCT at Hotel Novotel, Mumbai. The conference, unique and first of its kind in India, will bring together
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professionals from all functions supporting clinical trials, and provide a platform for increasing awareness and exchanging ideas on scientific and operational aspects of clinical research. The conference program has been designed to give a broad perspective on upstream and downstream activities that go into a well-designed and executed clinical study.
There are two pre-conference workshops on safety report writing and designing of clinical trials. The
safety writing workshop is being conducted by Dr. Suhasini Sharma of Sciformix Technologies and the
design workshop by Dr. Vishwanath Iyer of Novartis Oncology. Both of them are pre-eminent experts
in their respective fields and have a wealth of experience which they will be sharing. The workshops
would provide you with a forum where learning, exchanging of ideas and becoming aware of what the
others in the field are doing would be made feasible.
The conference has an agenda which mimics the normal flow of activities during a clinical trial design,
conduct, analyses and reporting. Plenary address to kick-off the conference is being given by Dr.
Rajendra Badwe from Tata Memorial Hospital. His expertise and sharing of ideas in doing clinical
research at a premier institute like Tata Memorial is going to be an experience which will benefit all of
us. Sessions on study planning, study execution, study analyses and reporting and interacting with
regulators will highlight the challenges and learnings that the expert set of speakers have had. There are
planned panel discussion sessions which will cover topics of current interest.
The conference and the workshops will provide you ample opportunities to meet the experts, network
with other colleagues and enhance your knowledge base.
I would like to thank the authors who have written articles for this newsletter. I know that it takes
efforts and requires special talent in putting thoughts down on paper. So special thanks to Stephen
Bamford from PhUSE, Ranganath Bandi from CliniRX, Harini Kunduru from BMS and Krishnendu
Biswas from Cognizant. Without the untiring editorial efforts of Bhaswati Mukherjee from BMS, Gloria
D'Souza from GSK and Shashidhar Joshi from Quintiles this newsletter would not be possible. As this
newsletter is a “face” of IASCT to the general public, heartfelt thanks to the three of you from the IASCT
governing council.
I take this opportunity to thank the Event Partners representing various organizations and training
institutions for their support in organizing this grand event. I look forward to their continued interest
and support in IASCT's growth. These include Cytel Statistical Software & Services Pvt. Ltd., Epoch
Research Institute Pvt. Ltd, Tech Observer, TAKE Solutions Global LLP, UnitedHealth Group
Information Services Pvt Ltd - i3 Mumbai Division, Novartis Pharmaceuticals (Oncology Division),
Sristek, GSK Pharmaceuticals Ltd., Quantum Enterprises Inc., Quanticate and Semler Research Center.
My sincere thanks to the IASCT organizing, event and admin committee members (Dr. Debjit Biswas,
Dr. Jayanti Gupta, MS Shubharekha, PS Jagannatha, Tushar Sakpal, Dr. Vishwanath Iyer, Prajakta Lale
Deven Babre, Manali Pendse , Anuradha, VijayKeerthi and Dr. Radhika Bobba) for the relentless efforts
in organizing this 3-day event.
I appreciate their diligence in choosing the expert speakers, persistence in reaching out to event
partners/participants and efforts in ensuring the best logistics for the event. Thanks to all those who are
contributing to the success of IASCT.
Warm regards,
Ashwini Mathur
President, IASCT
India Operations Head, Integrated Information Sciences
Novartis Healthcare Pvt. Ltd.
Venue: Hotel Novotel, MumbaiDate: January , 2011
e Two parallel One-day pre-conference workshops on safety report writing and clinical trial designs (January 20, 2011 )
e Two-day conference on exciting topics ranging from study design, execution, to analysis, reporting and submissions (January 21-22 , 2011)
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Clinical Trial Interfaces, 2011
Two parallel 1-day workshops on January 20th, 2011 from 9:30 am - 5:00 pm
I: Safety Report Writing by Dr. Suhasini Sharma (Sciformix)
II: Clinical Trial Designs by Dr. Vishwanath Iyer (Novartis)
CONFERENCE AGENDA
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Analysis & Reporting Chair: Dr. Shashidhar Rao (Novartis)
Ms.
Ms.
Mr.
Mr.
Dr.
Mr.
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I. Safety Report WritingDr. Suhasini Sharma
Sciformix
II: Clinical Trial Designs Dr. Vishwanath Iyer
Head, Oncology Biostatistics and Statistical Reporting
Novartis
Dr. Vishwanath (Mahesh) Iyer has a Ph.D. in Statistics from Temple University, Philadelphia. Mahesh has been involved in analyzing and reporting clinical trial data since 1998 with companies like Boehringer-Ingelheim and Bristol Myers Squibb, and specifically for Oncology studies since 2000. In addition, Mahesh has also been active in the statistical
Head, Scientific Writing
Dr. Suhasini Sharma is a physician with a post-graduate qualification (M.D.) in Pharmacology, and 25 years experience in pharmaceutical industry. She has headed Medical Affairs in various Indian and multinational companies such as Indoco Remedies, Searle India, Merind, Rexcel (a Ranbaxy Group company) and Goldshield Plc (a UK-based healthcare company), during which she has handled medical information, medico-marketing, training, regulatory support to new products, clinical research, drug safety and medical writing. Dr. Sharma has managed and overseen clinical trial operations (including a central ECG lab) for global clinical trials in India, in CRO / SMOs such as Quintiles India, and IRL-Synexus. Dr. Sharma currently heads Scientific Writing services at Sciformix Technologies. She provides oversight and subject matter expertise for all medical writing engagements for Sciformix's global clients and projects. Prior to joining Sciformix, she managed similar responsibilities at Indegne Lifesystems. At Sciformix, Dr. Sharma also provides medical review expertise for clinical documents, aggregate safety reports and risk management services.
Abstract :
Aggregate Safety Reports are important tools to evaluate risk-benefit ratio of drugs on an ongoing basis. They are required to be submitted on periodic basis during the developmental as well as post-marketing phase, and need to comply with ICH guidelines and PV regulations of different regions. Writing aggregate safety reports involves analysis of safety data during the review period, interpretation of this data in the light of already known safety profile and benefits of the drug (risk benefit analysis), and proposing actions for risk management, if needed.
The workshop will give the participants an overview of global drug safety regulations related to periodic reporting, familiarize them with different types of pre and post marketing periodic safety reports such as PSURs, PADERs, Annual Safety Reports, their structure and contents. There will be practical examples to acquaint the participants with sources of safety data, and how to analyze and present it for different type of reports, including ad hoc safety reports.
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Dr. Rajendra Badwe, MS, FACS
Dr. Badwe is Director as well as Professor and Head, Dept. of Surgical Oncology at the Tata Memorial Center, a premier national comprehensive cancer center for prevention, treatment and research.
Dr. Badwe has vast experience in Cancer surgery and breast cancer in India & UK and is one of the most highly regarded onco-surgeon in India. He has received several scholarships, fellowships & awards throughout his academic and professional life, including the Reach to Recovery International (RRI) medal that he was recently awarded by the International Union Against Cancer (UICC). He has also been a member of many national and international committees, task forces and initiatives such as WHO, UICC, Breast Health Global Initiative and ICMR.
Dr. Badwe has been keenly interested in conceptualizing and executing research projects to improve the outcome of interventions, especially in the area of breast cancer. His original research on Timing of Surgery in Operable Breast Cancer has changed treatment planning in UK and USA. He has over 75 publications in journals of international repute. He has been a reviewer and member of editorial board of journals such as Lancet, British Journal of Cancer, Cancer, Annals of Oncology and International Journal of Surgery.
Dr. Arun Nanivadekar, M.D., M.Sc.Dr. Nanivadekar was Medical & Research Director at Pfizer from 1974 to 1997, and before that at Wyeth from 1966 to 1974. He has followed his academic interests by participating in teaching and training programs at various medical schools and hospitals, editing “Practical Aspects of Clinical Trials”, contributing the series “Statistics for Clinicians” to JAPI, and being a reviewer to JAPI, IJP, and BMJ.
Since his retirement in 1997, Dr. Nanivadekar has been mentoring physicians and biomedical scientists in the drug industry, medical schools, hospitals, and private practice to promote the principles and practice of clinical research including, but not limited to, clinical trials.
research community with a primary focus on multiple comparison procedures. Currently, he heads the Oncology Biostatistics and Statistical Reporting group for Novartis in India. Mahesh is actively involved in teaching at multiple institutes in India, adjunct faculty at Institute of Ayurvedic and Integrated Medicine at Bangalore, serves on the Advisory Council of India for the DIA, on the Board of Studies for Statistics at Manipal University and is the co-editor for a pharmaceutical journal.
Abstract:
This workshop will discuss recent advances and innovative designs used in Phase I-III studies:
v Dose determining studies (3+3, CRM, BLRM, MCPmod)
v Clinical pharmacology studies (crossover, balance control, organ impairment, thorough QT)
v Phase II studies (2-stage, multi-stage, randomized Phase II, enrichment, seamless Phase II/III)
v Phase III studies (mutliplicity including gate-keeping, group-sequential, interim analyses)
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Study Design: The blueprint for clinical researchDr. Prathap Tharyan, MD, MRCPsych
Professor, Christian Medical College, Vellore
Dr. Prathap Tharyan is Professor of Psychiatry, and Associate Director at the Christian Medical College, Vellore, Tamil Nadu, India. He is also the Director of the South Asian Cochrane Network & Centre (www.cochrane-sacn.org), hosted at the Prof. BV Moses & Indian Council for Medical Research Centre for Advanced Research and Training in Evidence-Informed Healthcare at CMC Vellore. Dr. Tharyan is an Editor with the Cochrane Schizophrenia Group and a systematic review author with several other Cochrane review groups. He is a program partner and member of the executive of the DFID-funded Effective Healthcare Research Partnership Consortium (http://www.liv.ac.uk/evidence/) that seeks to provide evidence for the effects of interventions relevant to the MDGs and increase capacity for research synthesis in low and middle income countries. He is an Associate Editor with the open access journal Trials, The Journal of Evidence Based Medicine, and The Indian Journal of Medical EthicsDr. Tharyan is a member of the steering group of the Clinical Trials Registry-India (www.ctri.in) and a member of its technical working group. He is a member of the WHO Expert Panel on Guidelines Development, Ethics and Clinical Trials and a member of the WHO Advisory Group on Clinical Trials Registration and Reporting.
One of Dr. Tharyan's areas of interest is in facilitating improvements in the design, ethical and scientific conduct, reporting, interpretation and implementation of research evidence in India and other countries in the region and the role prospective registration of clinical trials may play in achieving this.
Abstract:
Randomized Controlled Trials (RCTs) are considered the study design least prone to bias, confounding and effects of chance in evaluating the efficacy and safety of interventions being evaluated for used in healthcare. However, this requires that critical aspects of trial design, execution, ethical conduct, execution, reporting and interpretation need to be incorporated into the trial protocol to ensure that the trial's results are transparent, accountable and reliable. Numerous examples exist where these critical elements were ignored or not complied with that have resulted in poorer health outcomes and the betrayal of trust placed in clinical research. This presentation will cover the critical aspects that can ensure that the results of clinical trials regain their status as the highest level of evidence that can inform health decisions and benefit of trial participants and civil society; and advance the interests of science, the sponsors and interpreters of research; and ethical and evidence-informed healthcare decision-making.
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Effective study planning : the key to successDr. Viraj Rajadhyaksha
Associate Director- Medical Liaison,
Sanofi-Aventis
Dr. Viraj Rajadhyaksha, is a pharmaceutical physician and has experience in conducting Phase II, III and IV global, regional and local clinical trials. He completed his MD from Seth GS Medical College and KEM Hospital, University of Mumbai, working as co-investigator in studies on acute coronary syndrome and hyperlipidemia, during which time he received the Gufic Award for Best Original Research on role of polyherbal formulation in hyperlipidemia. Currently enrolled on the MSc Pharmaceutical Medicine programme at the University of Surrey, UK, he is an affiliate member of the Faculty of Pharmaceutical Medicine, UK and the American College of Clinical Pharmacology. He has experience of conducting training programs for pharmaceutical physicians as well as clinical practitioners on research methodology in India and South Korea. He is a regular faculty member for courses at major institutes and universities in India, is co-ordinator of the Training Council of the Indian Society for Clinical Research (ISCR), is section editor for Perspectives in Clinical Research, and is a reviewer at the Indian Journal of Ophthalmology.
Abstract:
Clinical study planning is an important stage in the conduct of clinical trials. Several activities such as regulatory submissions, ethics submissions, site selection, training of sites and internal teams happens in this stage. Since study start up time is an important indicator for performance, project management of study planning is crucial. This will require defining key milestones before, having a proper risk management plan in place to prevent any adverse impact on the overall study start up. The session will cover practical aspects of clinical trial submission to regulators and ethics committees, site selection and training of teams.
Study Set-up: The Roadmap for Effective Data CollectionMs. Indrani Kakade
General Manager, Cognizant Technology Solutions
Ms. Indrani Kakade is an early adopter of Clinical Data Management Outsourcing to India with over 19 years of experience in pharmaceutical industry and 12+ years experience invested in Clinical Research and Data Management. She is a qualified Pharmacist, trained on ICH GCP and has strong knowledge and expertise in clinical data management operations along with transition, process and knowledge management across broad therapeutic areas and Trial Phases. She has successfully led and supported large projects/deployments and study transitions for Data Management operations for major international pharmaceuticals across multiple geographies & platforms and have successfully established and managed the STP (SOPs, training and Processes function) at Pfizer PGRD (India).
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In 2004, she successfully set up and is currently leading Training, Quality, Compliance and Audits function at Cognizant Life Sciences.
She has developed and successfully implemented concept of Quality Management Program for multiple work streams including Data Management, Statistical Programming & Analysis, Medical Writing and Pharmacovigilance and is actively involved in process improvement & re-engineering initiatives at organization and practice level in various areas like data management, Programming and Pharmacovigilance.
Abstract:
Clinical Trial Data should meet basic requirements of being analyzed timely, accurately and reported in a complete and conclusive manner. Short comings in data collection identified during conduct phase result in re-work, risk to project timelines, and delay in drug launches. Database migrations (database setup corrections) during conduct can affect study timelines adversely along with monetary loss to sponsor and CROs. Some common issues leading to delays could be weak Project Management, Protocol understanding gaps, Lack of Data Standards etc. Developing and regularly maintaining data standards library is an effective way to ensure consistent and complete data collection across studies. Study specific inputs and review from all stakeholders like Data manager, Study Statistician, Study Physician, Study Programmer etc. is important to cover all aspects of data collection in the study. It is important to identify gaps and plug them right at study set up phase. Also, clearly defined quality management plan plays a significant role to ensure incorporation of inputs from key stakeholders.
Selection and Training of Clinical Research Partners Ms. Celestine Juliet Rebello
Project Manager,
Cipla
Ms. Celestine Juliet Rebello is a project manager at Cipla Ltd. She has approximately 11 years of experience working in the clinical research field. She is a certified project management professional (PMP) and is a member of the Association of Clinical Research Professional (ACRP). She has given invited lectures at a number of conferences/workshops sponsored by the Drug Controller General of India/PMI and other organisations. She has a number of publications to her credit in various international journals.
Abstract:
The pharmaceutical industry makes widespread use of CROs and, most likely, this trend will increase in the coming years. Since outsourcing to CROs represents an integral part in developing drugs, it is important to understand specific outsourcing processes and techniques, such as project budgeting, CRO selection, managing studies, bid grids, and managing cost overruns. The importance of training needs for professionals to improve CRO selection and CRO project oversight will also be discussed.
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Dr. Liesel Dsilva
Senior Medical Advisor,
GlaxoSmithKline Pharmaceuticals Ltd.
Dr. Dsilva is a pulmonologist. She has completed her MD in chest
medicine from Grant Medical College, JJ Hospital Mumbai in 1996,
following which she was lecturer at Seth GS Medical College, KEM
Hospital, Mumbai. Thereafter, she began her private practice and was a
chest consultant at the Ram Krishna Mission Hospital, Mumbai. She also
worked as a medical advisor in the pharmaceutical industry. In 2005, she
proceeded to the Firestone Institute for Respiratory Health, McMaster
University in Canada to complete her 3 year post doc clinical research
fellowship. Her area of research was Non Invasive Markers of Airway
Inflammation particularly the use of sputum cell counts to manage Airways disease. She has
presented her work at the American Thoracic Society Conference and has published her work in
international journals. Upon her return to India in 2008, she joined GSK, Mumbai as a Senior
Medical Advisor. She is in-charge of local clinical studies and the respiratory portfolio at GSK.
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Pathway to Quality Management of Study DataMr. Deven Kishor Babre
Director in DM unit,
PharmaNet
After securing a postgraduate degree in life sciences from Mumbai
University, Mr. Deven Babre started his career as research investigator at
Tata Institute of social sciences (TISS) and worked there for almost three
years. After TISS, Deven managed medical information division at
Wockhardt Pharmaceutical. Thereafter, he joined Data Management unit of
Quintiles in India followed by DM unit of PharmaNet in India. With this he
has a total of about thirteen years of experience in Pharma and clinical data
management in these 2 international CROs where he was involved in
various roles including a role of Project Manager. He has also become a Certified Clinical Data
Manager (CCDM) from Society of Clinical Data Management (SCDM). Deven has been finding
time to be associated with various charitable institutes and is actively involved in providing
support to such organisations. His association for past 8 years with the diabetic detection centre
located in Chinchani (Tarapur) is worth mentioning.
Abstract:
Everything and anything in this world can be measured. There are benchmarks which are set
against which excellence can be measured. Quality may be defined as measure of excellence. To
measure quality there has to be some measure and it is equally important that defined standard
process/plan are followed. Quality control and quality assurance both are important. In clinical
data management (CDM), quality is one of the important elements with an expected error rate
critical variables 0% and Non-critical variables less than 0.05%. An attempt will be made to focus
on how one can ensure quality while generating/implementing Data Management Plan,
Standards for Database Design, Coding, Edit Check programming and testing, Query Resolution,
Reconciliation of external data e.g. Laboratory, Serious Adverse Event etc, and Database Lock
procedures. There are challenges currently faced by industry personnel in EDC studies which are
centering on quality will be discussed in this topic.
Clinical Project Management: Who's Monitoring the Monitor?
Dr. Sonal Vora
Director and Founder,
SYNERGETIK Learning Solutions
Dr. Sonal Vora has over 16 years of experience in the pharma and clinical research industry. She did her M.D. in pharmacology, and then worked at major healthcare companies like Lupin Laboratories, Novartis and Sanofi-Aventis. Having gained extensive experience in medico-marketing, regulatory affairs, medical publications and clinical research, she chose clinical research as her niche area.
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During her tenure in the industry, she was involved in biotechnology research studies and in original research studies on phytomedicines. She has conducted national and multinational clinical studies in various therapy areas including oncology, cardiology, thrombosis, diabetology, neurology and psychiatry. In her recent position as Sr. Director, Clinical Research Unit at Sanofi-Aventis, Dr. Vora was instrumental in expanding their global clinical operations in India. She scaled the unit up from three to 31 clinical research professionals within three years. During this tenure, while striving to create centres of clinical excellence, she has always been active in training students at institutes in India. She was awarded the 2004-2005 Gaurav Puraskar by Vanita Samaj for her outstanding contribution to clinical research in Modern and Traditional Medicine.
Dr. Vora has now started her own company called SYNERGETIK Learning Solutions, which is dedicated to providing training in clinical research to various stakeholders. This includes independent researchers or representatives of clinical research or medical teams of pharma and clinical research industries, institutions/organizations that impart training in clinical research, on-site clinical research teams in hospitals, ethics committees and regulatory offices.
More details can be found on her website at www.synergetiklearning.com
Abstract:
With the continuous increase in clinical trial complexities, there is a greater demand for a new
generation of project managers – those that can strategically drive projects and keep the bigger
picture in mind while managing/monitoring a clinical trial. This presentation gives an overview of
some challenges that can lead to project failure if not properly addressed, and highlights the new
role and responsibilities of the next generation project managers. It provides an insight into some
key skills that need to be acquired/strengthened to boost clinical project management and ensure
there is a balanced focus on projects, people and processes, especially in lieu of continuous changes
during different stages of the clinical trial. This ultimately paves the path for moving from project
management to project leadership, while enhancing the quality of clinical trial conduct and the
quality of relationships within the clinical study team.
Analysis Planning and Safety Monitoring: The Statistician as a TrialistDr. Ritwik Sinha
Statistician , Hewlett-Packard India
Dr. Ritwik Sinha was trained as a statistician in Presidency College, Calcutta and Indian Statistical Institute, where he did his Bachelors and Masters, respectively. After completing a PhD in Biostatistics from the Case Western Reserve University in Cleveland, Ohio, USA, Ritwik joined Bristol-Myers Squibb (BMS), in Connecticut, USA, as a Senior Research Biostatistician. At BMS, Ritwik worked as a statistician for multiple Phase I, II and III trials in Oncology for more than three years. In addition to the trial work, he also did projects on ways to analyze Duration of Response as an end-point and on the Bayesian longitudinal analysis of tumor burden data. Recently, he joined Hewlett-Packard India as a Statistician. At HP, he is working on using Survival analysis techniques in Marketing problems. Ritwik has a number of publications in peer reviewed journals.
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Abstract:
A Statistician plays a pivotal role in the conduct of a clinical trial; right from Study preparation, execution to reporting and filing. In this talk I will concentrate on the role of a Statistician in the study execution phase of a trial, in particular, on planning and monitoring. Some topics to be discussed include the Statistical Analysis Plans (timing and content), Analysis of Accrual and Projection of Timelines (statistical modeling to predict the time of the database locks), Safety Monitoring and Early Stopping.
Use of standards: can we really be analysis-ready? Mr. Murali Ganesan
Lead, Biostatistics and Programming,
Cognizant Life Sciences BPO
Mr. Murali Ganesan presently leads the Biostatistics and Programming at Cognizant Life Sciences BPO. After his M.Sc. Statistics (from IIT, Kanpur), he has worked with some of the leading pharmaceuticals – Pfizer, Novartis as a statistician and building & managing a team of statisticians & statistical programmers. He also supported Reliance life science as a consultant for their biostatistics and programming - clinical research service arm in addition t o s u p p o r t i n g their internal clinical and pre-clinical research. Apart from pharmaceuticals, he has worked with SAS Institute as a data mining consultant and worked across various industries – telecommunication, banking, insurance and retail.
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Data analysis : Demystifying the Jargon Dr. Shailaja Chilappagari
Consultant, Clinical Data Management,
Statistical Reporting and SAS Programming
Dr. Shailaja Chilappagari is a qualified Biostatistician with a PhD from University of South Carolina, USA. Her 12 years of experience with pharmaceutical community includes association with major companies such as Novartis, Dr. Reddy's Laboratories, Pfizer, USA where she lead, built and trained technical teams in the areas of clinical data management and statistical reporting. Shailaja is currently working as an independent consultant and trainer in the areas of Statistics, Clinical Data Management, statistical reporting and SAS Programming.
Abstract:
One of the statistical concepts that is very difficult for many people to grasp, yet critically important for an understanding of statistics, is the interpretation of results and cautions to be taken during interpretation of results including interim analysis results. Adaptive designs open a wide range of flexibility to clinical trials. Basic principles, merits and pitfalls of adaptive designs are reviewed.
The time to event data such as methods of survival analysis are required to analyze duration data. Common methods of survival analysis, namely, life-table, Kaplan-Meier, log-rank and Cox model are discussed.
Interpretation of Study Results – Science or Art? Dr. Vis Niranjan
President,
RxMD
Dr. Vis Niranjan, MD, is founder and President of RxMD, a biopharma and clinical drug development consulting company. Prior to RxMD, Vis was Assistant Professor at the University of Medicine and Dentistry in New Jersey, USA. Vis is Board Certified in Pediatrics and Critical Care with postdoctoral training in Molecular Biology and Translational Medicine. Vis graduated in Medicine from the University of Bombay. He lives in Chennai where he indulges in philosophy in his spare time.
Abstract:
The presentation will use several 'study results' as examples to address the question 'Science or Art'? The 'study results' will initially be scrutinized for programming errors and baseline comparability between treatment arms. Efficacy results ( Phase III superiority trial) will then be reviewed systematically for the primary end point (Intent to treat, per- protocol and robustness) and secondary end points. Safety data will be reviewed for frequently and infrequently reported events and laboratory data (measures of central tendency, shifts and outliers) followed by a conclusion on whether interpretation is a 'Science or Art'?
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Medical Response Documents: A new niche for medical writers
Dr. Bindu NarangAssociate Director, Global Medical Writing and Scientific Communications,i3 statprobe
Dr. Bindu Narang is Associate Director, Global Medical Writing and Scientific Communications at i3 statprobe, prior to which she was head of regulatory writing services for a global pharma company. She holds a postgraduate degree in Medicinal Chemistry, from the University of Mumbai, 1987. She started her career in 1987 in the pharmaceutical industry, providing medical communications services in various capacities.
Bindu has served as Founder Secretary-General of the Indian Chapter of The UCB Institute Of Allergy, and in that capacity presented on Statistics on Epidemiology of Allergy in India at a satellite meeting of the International Congress of Allergy and Immuno-allergology, ICACI, Cancun, 1997.
Abstract:
Medical communications cover a vast domain. Specifically, a pharmaceutical company needs to communicate to a variety of stakeholders internally, from finance, to marketing to the stockholders. The same company also needs to communicate to its customers –traditionally the medical fraternity, and more recently the end-user –the internet-savvy, literate consumers of its medicines.
Two reasons for communication to the consumer –one is the facebook-twitter-google-using generation, and two is drug defaulting sub-population indulging skipped doses, under dosing, forgotten dosing, and in India, under purchasing. Educating the consumer ensures full-course treatment, benefiting the prescriber, the patient and the pharma co.
But that's a topic by itself.
This presentation will focus on communication to the medical fraternity through letters –scientific response documents that are a result of critical literature evaluation, and offer both off-label and on label information to doctors, with a clear distinction between the two. The triggers for a response will be discussed –and the different roles of author and reviewer will be explained. CLEAR guidelines to evaluate literature searches, applying disclaimers and citing references are other elements of developing medical response documents. The rationale for pleiotropic uses of a drug, and how the discussion sections of study reports when suitable enriched, open new doors, new indications as a seed for planned serendipity …these will be touched upon. The Medical Response letters are completely scientific, and unbiased. A brief description of the Response Document Development process, followed by tips to identify key components of an effective communication, and the sequence of data sources to be used, based on principles of evidence based medicine will be reviewed.
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Dr. Radhika BobbaPartner Founder,
Anhvita BioPharma Consulting
Dr. Radhika Bobba has been associated with academia, the Indian Pharmaceutical and Clinical Research Industry for the last 20 years. Radhika set up Pharm Olam operations in 2002 as County Manager and Director of Clinical Operations. She has worked in a number of multinational pharmaceutical and CRO companies - Astra IDL, SmithKline Beecham, CIBA Vision, Allergan and Parexel. Her work experience spans medical affairs functions as well as business development, financial and human resource management, clinical operations, project management and regulatory.
Radhika completed her medical education from Government Medical College, Bellary and MD in Pharmacology from St John's Academy of Health Sciences, Bangalore.
She is an active member of DIA - India, Indian Society for Clinical Research and is a part of the Regulatory Council. She is actively working with regulatory bodies to ensure a good stem cell regulatory policy for India in line with international recommendations.
Regulatory interactions: engaging effectively for success
Dr. Manish Paliwal,
Head Regulatory Affairs,
Pfizer Limited
Dr. Manish Paliwal has obtained his MBBS degree from Rajasthan University in year 2000 and joined Pharmaceutical industry in June 2002. He has started his Pharma career with Cipla Limited and in Oct 2003, he has moved on to join Quintiles. He has worked as Regulatory Advisor and Medical Monitor. In June 2006, Manish has moved to Ranbaxy Laboratories Limited as Manager Regulatory Affairs and promoted as Senior Manager Regulatory Affairs. In Ranbaxy, he has provided tactical and strategic inputs in relation to registration and regulatory approvals for new products and business development. Currently, he is working with Pfizer Limited as Head Regulatory Affairs. He is responsible for various regulatory activities including clinical trials, product developments, generic drugs development etc. He is actively involved in interaction with regulatory agency in India.
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eCTD : a farewell to paper submissionMr. Vijay SrinivasanSr. Manager – Regulatory Services,
TAKE Solutions Ltd
Mr. Vijay has over 5 years experience in the life sciences industry, working both within big Pharma and as a consultant to the industry. He has specific expertise in Regulatory Submissions planning, compiling, publishing, & tracking, Electronic Document Management System (eDMS), Electronic Trial Master File Management (eTMF), SPL R4 Drug Listing and the implications of implementing electronic components within regulated business processes.
He currently manages global publishing teams in the creation and life cycle management of submissions (Paper, eCTD, NeES and other region specific formats) to several health authorities including FDA, EMEA, Health Canada and ROW countries.
Abstract:
The presentation will cover an introduction to Paper and eCTD Submissions and provide an overview of the limitations of paper submissions and compare them with the benefits of eCTD submissions. The audience will get an understanding of what it takes to migrate from paper based submissions to electronic and get a brief overview of the structure of an eCTD submission, its module wise contents and the guidelines associated with document e‐publishing.
Regulatory Filings : Ignorance Is Not BlissDr. Ranjani Nellore, Ph.D. RAC
President,
PharMantra Consulting Services
Dr. Ranjani Nellore, is a regulatory affairs certified professional with over 15 years of pharmaceutical industry experience in USA and India. She has submitted clinical trial applications and INDs to FDA, MHRA, TPD (Canada) and DCGI for several NCEs. She has participated in meetings with the EMEA and USFDA. She is an invited speaker at national and international meetings and renders customized training programs. She is the founder of PharMantra Consulting Services which provides regulatory consulting services to the global health science industry.
Abstract:
It is commonly understood that regulatory filings occur only at the end of a successful drug development program and are done to seek marketing approval. However, filings to regulatory authorities occur during the entire development lifecycle of a product, both before and after market approval. Beginning with the investigational new drug application that seeks permission to initiate studies in humans, a continuous process of information exchange guides the development of a molecule through various phases. Planned submissions may include additional protocols, amendments to manufacturing information, nonclinical study reports and annual updates. Unplanned interactions include meetings with regulators to resolve stalled programs and agree upon next steps. In every case, data is filed, response is sought and further action taken. This session will describe various regulatory filings and their role in the drug development and approval process.
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21
Comparative Effectiveness Research
Dr. Viraj Suvarna, MD, MSc Medical Director,Boehringer Ingelheim India Private Limited
Dr. Suvarna has more than 12 years of experience in the Indian pharmaceutical
industry, almost eleven years of which were in Pfizer (last position - Head,
Medical Operations providing strategic oversight and direction to Medical
Affairs, Medical Research Specialists, Medical Information, PV, Disease M a n a g e m e n t ,
External Medical Affairs, and Clinical Development including Non-Interventional Studies,
Outcomes Research and Investigator-Initiated Research).He did MBBS from Topiwala National
Medical College and BYL Nair Hospital, Mumbai (distinctions and prizes in Anatomy and
Pharmacology). Thereafter, he did MD Pharmacology from Grant Medical College and the Sir JJ
Group of Hospitals, Mumbai (First in Mumbai University) and MSc in Pharmaceutical Medicine
from Hibernia University, Dublin (first class). He is a peer reviewer for Indian Journal of
Pharmacology. Section Editor of Perspectives in Clinical Research (official journal of the Indian
Society of Clinical Research) and Member of Medical and Biotechnology Committee of OPPI.
Abstract:
Comparative effectiveness research (CER) is the conduct and synthesis of research comparing the
benefits and harms of different interventions and strategies to prevent, diagnose, treat and monitor
health conditions in “real world” settings. The purpose of CER is to assist consumers, clinicians,
purchasers, and policy makers to make informed decisions that will improve health care at both the
individual and population levels.
Comparative effectiveness research offers great promise for improving clinical decision making
and patient outcomes. However, there are concerns regarding the potential scope of such research
and how it may be used to influence healthcare delivery. Importantly it's not just processing
adverse events from RCTs in the pre-marketing phase but spontaneous adverse event reporting
and monitoring of the safety profile while it is being evaluated in post-marketing effectiveness
trials that will help determine the true risk to benefit.
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GREETINGS FROM PhUSE
Stephen Bamford
Since 2004, PhUSE has become one of the leading associations in the world for biometric
knowledge sharing. PhUSE is the worldwide voice that provides the Life Sciences industry
with the mechanism for sharing knowledge, defining and promoting industry standards,
with a view to furthering the provision of health-care information through technology. As
we enter 2011, PhUSE finds itself in a very exciting position. We have been partnering with
the FDA and together we have designed a Wiki for sharing code, algorithms and information
around data reporting. You can visit the PhUSE Wiki (and contribute) without being a
PhUSE Member. The web-address is http://www.phuse.eu/Wiki.aspx. Take a look at the
Wiki… See what you think… See the benefits it can bring and where you would be able to
contribute. PhUSE also has strong links with CDISC and you will find a lot of CDISC content
on our website.
As an association, we now have over 1,000 members (and we have grown to this size in just
three short years). Benefits to PhUSE Members include: discounts on the conference fees,
free access to worldwide single day events (these are mini conferences), online access to our
professional journal, copies of our quarterly newsletter, as well as access to our e-learning
material.
As a one off, I would like to share with you a version of our members’ newsletter:
http://content.yudu.com/A1q6zt/PhuseNewsWin2010. We are always looking for more
content from our members!
We have held six conferences. All the conferences have their papers available on the PhUSE
Website and the later conferences have their keynote presentations shared via video. These
are available for all to see at: http://www.phuse.eu/archive.aspx.
PhUSE has an objective to build a base for a worldwide voice of the industry, and PhUSE
would like India to be a part of it.
I have had a long career working with India and I first met Dr. Lele in 2001 when I went out to
visit the Pfizer Site in Mumbai. It is a pleasure, and an honor, to be asked to write an article
for the ECHOES newsletter and I do hope that during 2011, I will be able to visit India again
and have the opportunity to meet with you all – possibly at one of your events.
If you would like to find out more about PhUSE, please visit http://www.phuse.eu or e-mail
[email protected] if you have any questions or comments – or if you would like to get involved
in PhUSE by becoming our Regional Representative in India.
23
MAKE LIFE EASY WITH X AND PIPE
Ranganath Bandi,CliniRX Research Pvt. Ltd., USA
Harini Kunduru,Bristol Myers Squibb Company, USA
OBJECTIVEThe objective of this article is to help you understand how you can interact with your computer's operating system through SAS and trigger the operating system's commands to fetch the required information, to make your programming easier and more robust in nature. This article mainly deals with the usage of the X command statement and the SAS FILENAME statement in combination with the PIPE device type to interact with the host operating system and how we can use both methods to attain the same results. Though this article doesn't explain all the programming for how to automate these processes or writing a macro for doing the repeated work periodically, you will gain a basic idea based on the examples given below on how to go further in using your operating system's commands as per your requirements.
WHY TO USE AND WHERE TO USEGenerally, when we need to archive existing output or data that is present in a folder and create a new set of outputs we do it manually. This can be done by using the CMD commands in Windows and normal UNIX commands, but even this need to be done manually either by directly running the shell scripts or by executing each of the commands, but we can automate this process by writing all the commands in SAS and incorporate them into a SAS program. This article has examples for X and PIPE under both the Windows and UNIX operating systems. The examples are limited to 1) Creating a new archive directory, 2) Archiving/Copying the existing set of output to the new archive directory, 3) Changing the file attributes of the copied files in the new archive directory, 4) Acquiring file attributes such as the date time stamp of the files, 5) Reading the file attributes to a SAS dataset, 6) Triggering the Excel file/CSV file to open, saving the Excel/CSV file after the data is exported it and 7) Finally a comparison between the X statement and the PIPE device type.
The examples provided are executed under SAS 9.1 under Windows XP, SAS 8.2 under UNIX.
HOST: WINDOWS OPERATING SYSTEM
*** USING NOXWAIT NOXSYNC ****************;
OPTIONS NOXWAIT NOXSYNC;
The option NOXWAIT specifies that the command processor
returns automatically to the SAS session after the specified
command is executed. NOXSYNC is used for executing the
operating system commands asynchronously with your SAS
session
X STATEMENT PIPE DEVICE TYPE
***1) To create a new directory;
***2) Copying output to the new directory;
filename pipe_null_
infile
make ; ;
make; ;
"MKDIR C:\testst\progs\test3"data
run
24
***1) To create a new directory;
***2) Copying output to the new directory;
***If you want to delete the existing files in the directory;
***3) To change the attributes of the copied files in the new archived folder;
***4) Now fetch the file attributes;
***If you want to get even the owner of the output files;
X
X
X
X
X
X
;
;
COPY options are /Y, /A, /B etc.
;
Other options for DEL are /P, /F, /S, /A etc.
;
Other options for ATTRIB are -, A, S, H, /S, /D etc.
;
;
Other options for DIR are /B, /L, /S, /T etc.
"MKDIR C:\testst\progs\test2"
"copy C:\testst\progs\*.rtf C:\testst\progs\test2"
"del /q C:\testst\progs\*.rtf"
"ATTRIB +r C:\testst\progs\test2\*.*"
"Dir C:\testst\progs > C:\testst\progs\attributes.txt"
"Dir /q C:\testst\progs > C:\testst\progs\attributes.txt"
filename pipe
_null_infile
filename pipe_null_
infile
filename pipe_null_
infile
f i lename pipe
_null_infile
filename pipe
copying ;
; copying;
;
delete ; ;
delete ;;
attrib ; ; attrib;
;
a t t f i le ;
; attfile;
;
attfile ;
"copy C:\testst\progs\*.*rtf C:\testst\progs\test3"
"del /q C:\testst\progs\test3"
"Attrib +r C:\testst\progs\test3\*.*"
"Dir C:\ testst \progs > C:\testst\progs\test3\attributes.txt"
"Dir /q C:\testst\progs > C:\testst\progs\test3\attributes.txt"
data
run
data
run
data
run
data
run
***If you want to delete the existing files in the directory;
***3) To change the attributes of the copied files in the new archived folder;
***4) Now fetch the file attributes;
***If you want to get even the owner of the output files;
5) To read the file attributes into a SAS dataset by reading the text file attributes.txt created by the X statement, or the filename with PIPE device statement, or by fileref 'attfile' created by the filename statement.
%macro readatb(type=); %if %upcase(&type)=XCOMMAND or %upcase(&type)=PIPEEXT %then %do; Filename attfile “
demo; attfile = =len =eof; line len;
index(upcase(line), )>= ; moddate=scan(compbl(line), , ); time=scan(compbl(line), , ); pgname=scan(compbl(line), , );
;
%mend readtab;
C:\testst\progs\attributes.txt”; %end;
".RTF"' '
' '' '
data
run
infile truncover pad lrecl length end input if
32367$varying200.
11
25
6) To trigger Excel by using the X command X
filename dde
_null_
ile
put
put
;
xcel ;
;
xcel;
;
;
x=sleep( );
;
“C:\Program Files\Microsoft Office\Office12\excel.exe”
“EXCEL|SYSTEM”
’[open(“book1”)]’
‘[save.as(“C:\testst\progs\summary”)]’
data
run
1
6) Save the excel file after entering data
data
run
; xcel; ; ;
;
_null_fileputput
'[save()]''[quit()]'
25
The path reference to Excel .EXE will change as per the path of the .EXE file on your particular PC. You can export the file attributes which were read into the dataset demo to the Excel file created by using DDE Triplet. This is not explained in this article as it is not in the scope of it. After exporting the file attribute information to the Excel file, you can save it and close the application.
HOST: UNIX OPERATING SYSTEM
X STATEMENT PIPE DEVICE TYPE
***1) To create a directory;
***2) Copying to the directory;
***If you want to delete the existing files in the directory;
***3) To change the attributes of the copied files in the
archived folder;
***4) Now fetch the file attributes;
***To fetch the owner of the files;
***5) Reading the file attributes into a dataset;
***6) Create CSV file using filename;
Create blank files:
X
X
X
X
X
X
infile dlm
length
input
format
X
filename pipe
filename
_null_
infile
file
input
put _infile_
;
;
Use cp -p option to preserve the time stamp.
;
;
u - user, g - group, o - other and a - all
r - read, w - write, x - execute. The above statement removes
write and execute permissions from all rtf files.
;
;
outf;
“ = ;
filenm $ permisn $ ;
permisn $ n1 $ user $ group $ size $ month $ day $
year $ filenm $ ;
filedate=input(compress(day||month||year), );
filedate ;
;
;
copyin ;
copyout ;
;
copyin ;
copyout;
;
;
;
"mkdir /my/unix/newdir"
"cp /my/unix/*.rtf /my/unix/newdir/."
"rm /my/unix/*.rtf"
"chmod ugo-wx /my/unix/newdir/*.rtf"
"cd /my/unix/newdir; ls -l *.rtf > fileinfo.txt"
" ls -al *.rtf | awk '{print $3}'"
fileinfo.txt" ' '
'touch newfile.csv'
"ls -l"
"file.csv"
data
run
data
run
50 10
date9.
date9.
***1) To create a directory;
***2) Copying to the directory;
***If you want to delete the existing files in the directory;
***3) To change the attributes of the copied files in the archived folder;
***4) Now fetch the file attributes;
***To fetch the owner of the files;
***5) Reading the file attributes into a dataset;
filename pipe_null_
infile
filename pipe
filename pipe
filename pipe
filename pipe
filename pipe
infile dlmlengthinput
format
makeinfo ; ;
makeinfo;;
Note: Use data _null_ statements as above to execute any filename statement.
copyfl ;
delfl ;
permi ;
fileinfo ;
owner ;
outf; fileinfo = ; filenm $ permisn $ ; permisn $ n1 $ user $ group $ size $ month $ day $ year $ filenm $ ; filedate=input(compress(day||month||year), ); filedate ;
"mkdir /my/unix/newdir"
"cp /my/unix/*.rtf /my/unix/newdir/."
"rm /my/unix/*.rtf"
"chmod ugo-wx /my/unix/newdir/*.rtf"
'ls -l /my/unix/newdir/*.rtf '
" ls -al *.rtf | awk '{print $3}'"
' '
data
run
data
run;
80 10
date9.date9.
26
7) COMPARISON OF X vs. FILENAME STATEMENT PIPE DEVICE TYPE
1) We can give multiple commands in single X statement unlike the Filename option which
only allow one UNIX/DOS command in single filename statement.
2) The Filename option with pipe device always creates temporary output that can be used
later in the programming while with the X statement we can create permanent output files
only.
ACKNOWLEDGEMENT
We would like to thank Patricia Rice, Sr. Director Statistics, CliniRX USA for proof reading
the draft document of the article.
REFERENCES
1) Na Li, Applications for Running DOS Commands within SAS, Article PO13.
2) Windows Help Documentation for DOS Commands.
3) UNIX Help Documentation for UNIX Commands.
******* IDEA OF RANDOMIZATION ********
Source: Internet
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28
Adaptive Allocation Rules in Clinical Trials
Krishnendu Biswas Service Delivery Manager, Biostatistics.
Cognizant Technology Solutions
Authorities of clinical trial design generally recommend allocating patients to equal- sized treatment groups. The successful and efficient recruitment of patients for clinical trials is an increasingly difficult challenge. Randomized clinical trials allocating equal number of subjects to each treatment are regarded as “Gold Standard” for comparing treatments.
Equal Allocation Rule
This is the simplest rule where the patients are assigned to one the treatments with equal probability. But equal allocation suffers from several drawbacks. If one treatment is better than the other, then half of the subjects in the clinical trial will receive an inferior treatment. Hence equal allocation might not be most efficient for estimating the parameters.
These drawbacks are somehow overcome by propositions of several Adaptive Allocation Rules. These Adaptive Allocation rules are designs that skew the allocation in the course of trial. This article will be discussing Biased coin designs, Play the winner, Randomized play the winner rule (Wei and Durham 1978 and Wei 1979), and Drop the loser. While discussing let's assume that we have two treatments A and B. Patients arrive sequentially in a Clinical Trial and are to be allocated to one of the treatments.
Biased coin design
Efron (1971) introduced Biased Coin Design (p) to compromise between complete randomization and perfect balance to reduce experimental bias and to increase the precision of inference. The rule is described in the following manner.
Suppose each time an eligible subject arrives, one calculates D = (number of subjects previously assigned to Treatment A) – (number of subjects previously assigned to Treatment B). Then the following rule is used: if D = 0, assign this subject to either treatment with probability ½; if D < 0, assign the subject to treatment A with probability p; if D < ½, assign to treatment B with probability p. A value of p is used so that p >= ½. But this rule cannot discriminate between large absolute values of D versus small values e.g. (i) 2 A's and 0 B have been assigned & (ii) 11 A's and 9 B's assigned; in both the cases D = 2 but the imbalance between treatment groups in (ii) is much less serious than in (i).
Play the winner
For a sequence of entering patients the first one is treated by tossing a fair coin (i.e. with probability ½ for both treatments to be used for the first entering patient). For any patient, if the response is a success we treat the next entering patient by the same treatment. On the other hand, if the response is a failure we treat the next patient by the other treatment.Conceptually it means we are sticking to a 'good' treatment for the next stage. Mathematically the process has some renewal property. If we know that the i-th patient is treated by treatment A (say), then for any fixed j, the allocation pattern of the (i+j)-th patient is stochastically the same whatever be the value of i.
The biggest objection to this is it is too subjective – the response of one patient determines the allocation of the next patient. In practice response of one patient may be an outlier, and that should not have much weightage, at least that of fully determining another's treatment. One
29
has to suitably decrease the weight of the response of a particular patient in the allocation procedure.
Suppose πi is the conditional probability that the i-th patient is treated by treatment A given all assignment history and previous response history. Then for PW rule πi is only a function of previous assignment and response, so this can take only values, 1 or 0.
Randomized play the winner
Randomization of the PW rule results a value of πi within its permissible range excluding 0 and 1. Moreover it takes into account all the previous histories provided by the earlier patients for assignment of the new patient.
Let us start with an urn having 2α balls initially, α balls of a color representing treatment A and α balls of a color representing treatment B. Thus initially (when we have no prior information about the superiority of any particular treatment over the other) the urn shows a 50:50 balanced pattern to the two treatments. For any entering patient the urn represents the allocation pattern and our object is to draw a ball from the urn, replace it immediately to the urn and allocate the entering patient to the treatment represented by the color of the draw ball. For any treated patient we add β balls suitably depending on his/her response. If the response of a patient is a success we add β balls of the same kind in the urn. On the other hand, if the response is a failure we add β balls of the opposite kind in the urn. This process is continued.
The idea is to skew the urn in favor of the treatment which will be the eventual winner and provide some ethical gain through it.
Though appealing ethically and statistically, adaptive schemes are not widely used as these designs suffer from high variability in the allocation proportion. One reason is that these random allocation schemes are based on random responses from a patient and can be highly variable.
In a latest paper, “a play – the – winner – type urn design with reduced variability” by Ivanova. A (2003); a new adaptive allocation rule has been proposed. The rule is called “drop – the – loser “, it randomizes subjects in the course of a trial comparing treatments with dichotomous outcomes. The rule tends to assign more patients to better treatments with the same limiting proportion as the randomized – play – the winner rule. The new design has significantly less variability than other existing rules. Moreover the rule is attractive for its simplicity.
Drop the loser
Consider an urn with three types of balls, type 1 and type 2 balls represent the treatment type balls and type 3 balls are so called immigration balls. Initially we assume the urn composition to be (Z10, Z20, a) a > 0. Then the rule is as follows:
When a patient arrives a ball is removed randomly from the urn. If it is an immigration ball then return it to the urn along with two additional balls of each treatment type. This process is continued until we get a treatment type ball. If a type i ball is drawn then the patient is assigned to treatment i, i = 1, 2 and the outcome for the patient is observed. If the outcome is a success then the ball is returned to favor the successful treatment. On the other hand if failure occurs the ball is not returned to the urn i.e. we are dropping the loser.
Mathematically it means that we are going through a complicated dependent process which may lead us to use the strong martingale theory.
30
Conclusions
It can be shown that Drop – the – loser rule is substantially less variable and has a slightly higher rate of convergence than others. Reduced variability leads to improved power. In fact, the drop – the – loser rule has better power than the other rules. For some values of success probabilities this has a double advantage over conventional equal allocation in that it has better power and assigns more subjects to better treatments. All the previous discussions are carried out assuming instantaneous patient responses. Often responses may be delayed so that some of the previous responses may not be obtained. In such situation we should incorporate such delayed responses in our model.
References1. Ivanova, A. (2003). A play-the-winner type urn model with reduced variability. Metrika
58: 1-13
2. Coad DS , Ivanova A. (2001). Bias caculations for adaptive designs. Sequential analysis. 20: 91- 116
3. Zelen M (1969). Play the winner rule and the controlled Clinical Trial. J. Journal of American Statistical Association, 64: 131 – 146
4. Efron B. (1971). Forcing sequential experiments to be balanced. Biometrika, 58: 403–417
5. Wei L. J. (1979). The generalized Polya's urn design for sequential medical trials. Annals of Statistics , 7: 291-296
6. Wei LJ, Durham SD (1978). The randomized play-the-winner rule in medical trials. Journal of American Statistical Association, 85: 156-162.
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SUMMARY OF PREVIOUS IASCT EVENTS
The SAS Users Conference 2010
Venue : Novotel, Hyderabad
Date : 28‐Aug‐2010
This SAS Co-Sponsored event was designed to provide a platform for SAS users in the health
science industry to present, and exchange information on unique innovative advances in SAS
programming. The talks principally focused on unknown or lesser well-known SAS functionalities
to solve complex, every day problems.
The day began with an opening note from Dr. Mahesh Iyer, Group Head, Oncology Biometrics, Novartis HealthCare. He stressed on the importance of keeping in tandem with the changing regulatory requirements and advancements in technologies. This was followed by a very informative and enlightening session delivered by experts from various organizations. Following were the topics presented:
Explore, experiment and innovate using RTF control words - Rubia Shaik, Novartis
The new FCMP procedure – power to the user – Jino Joseph, GSK
Tag sets in SAS 9.1 – a new dimension in report customization – Bhargavi Srinivasan,
Quintiles
SAS code generator – an innovative approach –Shradha, Cytel
Utility Macros – Page Breaks, Number of Decimals – Alistair D'Souza, Sciformix
Presentation from SAS India on SAS DI
Proc Report using Call Execute – Somayajulu, Novartis
Advancements in SAS - Kailash, Quintiles
The conference hit the spot in enlightening the audience with a spectrum of information on diverse
and recent advancements in SAS Programming.
Compiled by
Jino Joseph,
GSK
Send comments, suggestions and submissions to
[email protected]; gloria.g.d'[email protected];
33
Clinical Trial Interfaces, 2011 by IASCT
is proud to be supported by
www.iasct.net
