Thank you to everyone who attended our recent webinar on protocol design and development. During the webinar, we weren't able to get to all of the questions. Below, Dr. Shoemaker and Dr. Kesler have answered the remainder of the questions.
If you didn't have an opportunity to attend the webinar, it is now available on demand.
Why do you think the adoption of the PRM has been so long in the coming?
The Pharmaceutical industry is nototiously slow to adopt novel techniques due to the siloed structure and because the current protocol development process has been in place for decades. Not until the current protocol authors understand the concept of CDISC and the importance of generating consistent data across their program will their methods change. That will only happen if protocol authors are responsible for writing marketing applications.
What are the major consequences of redundancy in the protocol?
Inefficiency due to the need for redundant editing to ensure replacement of all instances and ultimately the cost of amendments if the redundant information is not edited correctly.
How long does it take to properly develop a clinical protocol?
Given adequate time to develop a novel protocol for a new indication with a new molecular entity depends on coordinating the time of all the people whose input is required. Depending upon peoples' priorities and availability it typically takes between one and two months.
If I am developing my drug as an add-on to an approved drug, why not conduct Phase I in patients (not healthy volunteers) taking stable doses of the approved drug? I want to know the safety of a range of doses of study drug when so administered. Pros/cons
Pros are that you save time and money with this approach. Cons are that you won't know if a safety event is due to your product, the approved product, or the combination. You also won't know whether the patients' compromised condition contributed in any way to the safety event.
It is said that no amount of good monitoring can fix a bad protocol. Do you have an example of such a situation and what should the monitoring team look out for to avoid such a situation?
By the time the monitoring team starts reviewing the data at the site or in house it is too late, the die has already been cast by the design of the clinical study. The monitors should endeavor to participate in protocol design to assist in mistakes made at this stage. Otherwise they can only make recommendations to amend the protocol if they see the data being generated is not answering the intended objectives of the study.
Is it advisable to write into the protocol the duration of acceptable periods during which study drug may be suspended without automatically discontinuing the subject?
If your study drug planned to be titrated within subject (e.g. some hypertension drugs) then it is advisable to have not only a duration of suspension, but also dose escalation/de-escalation processes as well. For other situations where study drug is being suspended due to concomitant events, like hospitalization, it is also advisable to have windows for the duration of acceptable suspension. If you don't have expected reasons for suspension and don't expect it to happen often, then it is probably a level of detail you don't need.
Do you have any template?
Yes we have an internal protocol template that we provide to all our clients developing protocols.
Please remind us what data we need to provide for you to determine a sample size for a clinical trial.
It depends on the type of primary outcome. If it is dichotomous, you need to provide the expected percent responding in both the active and control arms. If it is continuous, you'll need to provide the expected mean and variance (or standard deviation) for each group, or the expected difference in means. Other types of outcomes (e.g. survival, multiple categories) require additional information. All studies need a Type I level (alpha) specified as well as the desired power of the study. Estimates of the rate of dropout are also needed for most studies.
We will be conducting another webinar on Thursday March 17th at 1 PM ET on Clinical Research Statistics for Non-statisticians. We will go into more depth about sample size calculations during that webinar.
Is this protocol process impacted if/when combo solutions are involved? Combo is defined as drug/sensor based, or subcutaneous drug-illuting solutions.
Not really. Obviously you have to understand the combination product and its properties to the same extent that you understand your drug from a nonclinical and manufacturing properties perspective.
When is unblinded medical review warranted in Phase 2 studies?
There is a new guidance from FDA as of December 2015 advocating the use of a Safety Assessment Committee to review unblinded data from the totality of the data on your product and this should be implemented with the advent of controlled studies in Phase 2.
When can multiple repeat dose safety study be done with parallel dosing of multiple dose groups?
Never. Parallel dosing of multiple dose groups can be done for efficacy comparisons after safety has been demonstrated.
What is the proper endpoint for oncology trial now? it is overall response, tumor shrink, survival or quality of life?
It depends on the type of tumor being studied, but overall response is the preferred SURROGATE clinical endpoint in most cases for accelerated approval with follow-up measurement of survival used to validate this SURROGATE clinical endpoint. Quality of Life is usually montored with one of several patient reported outcomes (PROs) as a secondary clnical endpoint.
You mentiond that CDISC was advising avoidance of the use of "Day 0" terminology to describe intervention date and that this would be required after a certain date. Can you please restate when this goes into effect?
Trials started after December 2016.
Do you know of any company which can offfer to write protocol for their product?
David Shoemaker, Ph.D.
Senior Vice President R&D
Dr. David Shoemaker has more than 25 years of experience in research and pharmaceutical development. He has served as a Program Leader or Advisor for multi-disciplinary program teams and has been involved with products at all stages of the development process. Dr. Shoemaker has managed the regulatory strategy for programs involving multiple therapeutic areas, including hematology, oncology, cardiology, pulmonology, infectious diseases, genetic enzyme deficiencies, antitoxins, and anti-bioterrorism agents. He has extensive experience in the preparation and filing of all types of regulatory submissions including primary responsibility for four BLAs and three NDAs. He has managed or contributed to more than two dozen NDAs, BLAs, and MAAs. Dr. Shoemaker has moderated dozens of regulatory authority meetings for all stages of development. His primary areas of expertise include clinical study design and regulatory strategy for development of novel drug and biological products.
Karen Kesler, Ph.D.
Assistant Vice President Operations
Dr. Karen Kesler earned both a Master’s and Doctoral degree in Biostatistics from the University of North Carolina at Chapel Hill and has over 20 years of experience in the industry. Dr. Kesler currently serves as the Primary Investigator of the Statistics and Data Management Center for a NIH sponsored coordinating center researching asthma, allergies, autoimmune disorders, and solid organ transplant. Dr. Kesler is deeply involved in researching more efficient Phase II and III trials and has led many adaptive studies including sample size recalculations, pruning designs, Bayesian dose escalation studies, and adaptive randomizations. She has given numerous professional presentations and has over 25 publications and manuscripts to her credit.