Category: Accrual problems in clinical trials (created 2007-08-21). These pages cover some of the issues associated with accrual problems, research studies that accrue patients too slowly. Researchers have the dangerous tendency to provide overly ambitious goals for their clinical trials. They will suggest that they can recruit an unrealistically large number of patients in an unrealistically tight time frame. I am working with a colleague, Byron Gajewski, to develop some Bayesian models for waiting times between successive patients that will allow for more careful planning of the time frame for a clinical trial. These models allow the researchers to track patients accrual rates and react quickly if patient enrollment is suffering. Also see Category: Adverse events in clinical trials, Category: Bayesian statistics. Other entries about accrual problems in clinical trials can be found in the accrual problems page at the StATS website.

2008

  1. P.Mean: Data that IRBs should collect about themselves (created 2009-05-22). Somone on the IRBForum (TS) asked about what type of reports that an IRB should provide. There were a lot of good comments. I encouraged a data centric approach to reporting. Here's what I wrote.
  2. P.Mean: Plug for accrual research (created 2008-07-24). I received a request for use of material from my old website. It's a bit tricky right now, but I hope to have things resolved soon. The person inquiring was the owner of a company that specializes in clinical research and clinical data management. I thought it wouldn't hurt to mention some of the work that Byron Gajewski and I have done in accrual rates. Here's what I wrote.
  3. P.Mean: Cytel software has developed a Poisson model for predicting accrual (created 2008-07-09). I attended a web seminar by Jeff Palmer, Cytel Corporation, about Bayesian methods in adaptive clinical trials. It was a very good seminar, and I should try to summarize some of the major points sometime. One of the figures, though, caught my attention. It showed a projection of future accrual based on a Poisson distribution.

Outside resources:

Classical and Adaptive Clinical Trial Designs Using ExpDesign Studio. Mark Chang (2008) New York, NY: Wiley-Interscience. [BookFinder4U link] Excerpt: This book introduces pharmaceutical statisticians, scientists, researchers, and others to ExpDesign Studio software for classical and adaptive designs of clinical trials. It includes the Professional Version 5.0 of ExpDesign Studio software that frees pharmaceutical professionals to focus on drug development and related challenges while the software handles the essential calculations and computations. After a hands-on introduction to the software and an overview of clinical trial designs encompassing numerous variations, Classical and Adaptive Clinical Trial Designs Using ExpDesign Studio: * Covers both classical and adaptive clinical trial designs, monitoring, and analyses * Explains various classical and adaptive designs including groupsequential, sample-size reestimation, dropping-loser, biomarker-adaptive, and response-adaptive randomization designs * Includes instructions for over 100 design methods that have been implemented in ExpDesign Studio and step-by-step demos as well as real-world examples * Emphasizes applications, yet covers key mathematical formulations * Introduces readers to additional toolkits in ExpDesign Studio that help in designing, monitoring, and analyzing trials, such as the adaptive monitor, graphical calculator, the probability calculator, the confidence interval calculator, and more * Presents comprehensive technique notes for sample-size calculation methods, grouped by the number of arms, the trial endpoint, and the analysis basis Written with practitioners in mind, this is an ideal self-study guide for not only statisticians, but also scientists, researchers, and professionals in the pharmaceutical industry, contract research organizations (CROs), and regulatory bodies. It's also a go-to reference for biostatisticians, pharmacokinetic specialists, and principal investigators involved in clinical trials.

ExpDesign Studio: Powerful, User-friendly. Affordable. CTriSoft International. Excerpt: ExpDesign StudioTM is an integrated environment for designing experiments or clinical trials. It is a powerful and user-friendly statistical software product that has integrated 8 main components: Classical Design, Sequential Design, Multi-Stage Design, Dose-Escalation Design, Adaptive Design, Adaptive Trial Monitoring, Dose-Escalation Trial Monitoring modules, and Adaptive Trial Simulator. In addition, ExpDesign Randomizor can generate random variates from different distributions. ExpDesign Toolkit provides features for distributional calculation, confidence intervals, function and data plotting. This website was last verified on 2008-URL: www.ctrisoft.net

Modelling, prediction and adaptive adjustment of recruitment in multicentre trials. VV Anisimov, VV Fedorov. Statistics in Medicine 2007: 26; 4958-4975. [Medline] [Abstract]. Description: This paper uses a Poisson process to predict accrual rates in a multi-center clinical trial. It also calculates the number of additional centers to add in order to finish the study by a specified date with a reasonable probability.

Physicians' reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. KM Taylor, RG Margolese, CL Soskolne. N Engl J Med 1984: 310(21); 1363-7. Description: This article presents results of a survey asking physicians in a major clinical trial why they were not entering all eligible patients in that trial. The major reasons were concern about how the trial might alter the doctor-patient relationship, difficulty with informed consent, and discomfort with discussions about uncertainty.

Creative Commons License All of the material above this paragraph is licensed under a Creative Commons Attribution 3.0 United States License. This page was written by Steve Simon and was last modified on 2009-05-22. The material below this paragraph links to my old website, StATS. Although I wrote all of the material listed below, my ex-employer, Children's Mercy Hospital, has claimed copyright ownership of this material. The brief excerpts shown here are included under the fair use provisions of U.S. Copyright laws.

2008

  1. StATS: Eliciting a prior distribution for rejection/refusal rates (June 7, 2008). I got a question about the Bayesian model for rejection/refusal rates. I had used three prior distributions in my calculations, a Beta(10,40), a Beta(45,5), and a Beta(25,25). The question was, how did I select those prior distributions.
  2. StATS: A simple Bayesian model for exponential accrual times (May 26, 2008). Here is a simple Bayesian model for exponential accrual times. This model will help researchers to plan the estimated duration of a clinical trial. The same model will also allow the researcher to monitor the accrual during the trial itself and develop revised estimates for the duration or the sample size.
  3. StATS: Why does a Bayesian approach make sense for monitoring accrual? (May 8, 2008). I'm working with Byron Gajewski to develop some models for monitoring the progress of clinical trials. Too many researchers overpromise and underdeliver on the planned sample size and the planned completion date of their research This leads to serious delays in the research and inadequate precision and power when the research is completed. We want to develop some tools that will let researchers plan the pattern of patient accrual in their studies. These tools will also let the researchers carefully monitor the progress of their studies and let them take action quickly if accrual rates are suffering. We've adopted a Bayesian approach for these tools. While a Bayesian approach to Statistics is controversial, we feel that there should be no controversy with regard to using Bayesian models in modeling accrual.
  4. StATS: Slipped deadlines and sample size shortfalls in a random sample of research studies (May 7, 2008). There is a limited amount of data out there that suggests that many researchers overpromise on the planned sample size and completion date and underdeliver. About a year ago, I received a small grant to study the proportion of studies at Children's Mercy Hospital (CMH) that failed to meet the proposed completion deadlines, that failed to recruit the promised number of patients or both. Here is a brief summary of these results.
  5. StATS: Monitoring refusals and exclusions in a clinical trial (May 1, 2008). Someone sent me an email asking about the work that Byron Gajewski and I have done on monitoring accrual patterns in clinical trials. She had been doing something similar at her job and wanted to see if we could collaborate. In her situation, the major issue was the number of patients who made an initial contact but did not keep their first appointment, the number of patients who kept the appointment, but refused to sign the consent form once they realized what the study was about, and the number of patients who did sign the consent form, but who did not meet the inclusion criteria once the initial screening was done.

    2007
     
  6. StATS: Case study of accrual in a clinical trial (September 11, 2007). I received additional accrual data on a clinical trial I am monitoring. To review, the trial started on August 28, 2007 and will continue until January 31, 2008, for a total of 22 weeks. The researcher thinks that he might be able to get 3 patients per week over a 22 week trial (66 total), but he is very confident that he would get at least 2 patients per week (44 total). The confidence in the estimate of 3 patients per week was rated as 5 on a 10 point scale. After one week, a single patient has entered the study. No patients enter on weeks 2, 3, or 4. On week 5, three patients enter the study. On week 6, one more patient enters for a total of 5 patients.
  7. StATS: An alternate way of viewing accrual (October 2, 2007). I was talking about a project with a fellow in Emergency Medicine and during the discussion realized a different way of looking at accrual in a clinical trial. She plans to look how accurately EKGs are read by physicians in the Emergency Room. I showed her some of the work that Byron Gajewski and I had done on planning and monitoring accrual rates. She pointed at that accrual was not a problem here in that the number of EKGs that are processed in the ER is known with very high precision. The problem, of course, is that the physicians who participate in the study have to fill out a small amount of additional paperwork for the research. While this is not an intrusive amount of work and she is going to work hard to promote this research project, there will some physicians at some times who will not fill out the extra research paperwork, or will fill it out so incompletely as to make the EKG unusable in the research. The ER is a busy and hectic place and it is difficult to get complete data, even when the ER doctors are trying their best to help with the research.
  8. StATS: Case study of accrual in a clinical trial (September 11, 2007). Someone came by today with a project where he wants to monitor the accrual in a clinical trial. The trial started on August 28, 2007 and will continue until January 31, 2008, for a total of 22 weeks. He thinks that he might be able to get 3 patients per week over a 22 week trial (66 total), but he is very confident that he would get at least 2 patients per week (44 total).
  9. StATS: Accrual grant, Round 3 (August 21, 2007). Last year, I applied for a Kansas City Area Life Sciences Institute (KCALSI) Research Development grant. It was not funded, but a subsequent grant that I submitted to the Katherine B. Richardson foundation was funded. Both grants are rather small, intended as seed money to encourage development of a larger scale project which might attract funding from the NIH or a large foundation. I want to revise the KCALSI grant and re-submit it for the 2007 cycle.

    2006
     
  10. StATS: A simple Bayesian model for accrual (November 17, 2006). Suppose you are a researcher in charge of a long term study. You plan to collect data on 120 patients. The goal is to finish your study in ten years, which means getting 12 patients per year or one every thirty days on average. Recruiting patients though appears to be harder than you had expected. You recruited your first patient on day 56, 26 days behind schedule. The second patient is not recruited until day 93. About two years into the study (day 768), you have just recruited your 10th patient. It looks like recruitment might be behind schedule. Is it time to take action? A Bayesian model of accrual times can help you to discern whether recruitment is behind schedule and project an estimated completion date allowing for uncertainty.
  11. StATS: My second grant, part 3 (October 2, 2006). I just finished my second grant, which I gave the title "Estimating delays in completion of IRB approved and KBR supported research studies" The two acronyms, IRB and KBR should be familiar to the group I am applying to. IRB stands for Institutional Review Board and KBR represents an internal grant mechanism here at Children's Mercy Hospital to support initial research efforts. The initials KBR stand for Katherine Berry Richardson, who is one of the initial founders in Children's Mercy Hospital.
  12. StATS: My second grant, part 2 (September 13, 2006). I took a three day workshop on grant writing and prepared a draft grant as part of the student exercises in that class. It's not in the format that I need to use, but it outlines most of the goals and efforts of my proposed work. I wrote about accrual problems in clinical trials.
  13. StATS: My second grant (July 26, 2006). I'm in the final stretch of writing a grant to submit to the Kansas City Area Life Sciences Institute. I am already thinking "what is my next step?" One possibility would be to run a small study that will provide hard numbers to support a commonly expressed belief that most research studies fall behind schedule and fail to get anything close to the targeted sample sizes.
  14. StATS: Initial work on the KCALSI grant (July 17, 2006). I am submitting a grant in response to a KCALSI RFP. According to the RFP, the general structure of the grant should follow the structure used by NIH. Here is a review of the structure of a typical NIH grant.
  15. StATS: Early detection of accrual problems in clinical trials (June 30, 2006). The most common reason why clinical trials fail is that they fall well below their goals for patient accrual. Institutional Review Boards (IRBs) are charged with the continual monitoring of clinical trials and they need to identify when these trials encounter problems with accrual. When do they "jump the shark" so to speak?
  16. StATS: Applications of the CUSUM chart (June 20, 2006). I am interested in investigating the use of CUSUM charts in monitoring accrual rates, drop out rates, and adverse event rates in a clinical trial. Some references which I might cite in a literature review are listed here.
  17. StATS: Monitoring accrual rates (May 30, 2006). This scenario is based on real data, but has been adapted slightly to serve as an illustration of the use of control charts in monitoring a clinical trial. Suppose a clinical trial was set up in 1997 and the goal was to recruit one patient per month over a ten year period, for a total sample size of 120 patients. Here are the dates of recruitment for the first 42 patients.

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