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Not Just Tiny Humans: Considerations for Conducting Pediatric Clinical Trials

Posted by Brook White on Tue, Apr 25, 2017 @ 09:43 AM
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Jamie Arnott, BSN, RN--Project DirectorCaitlin Hirschman, RN, BSN--Clinical Team LeadProject Director Jamie Arnott, RN, BSN and Clinical Team Lead Caitlin Hirschman, RN, BSN have extensive experience in pediatric clinical research including recent studies in rare diseases and diseases with a seasonal component.

When it comes to the conduct of pediatric clinical trials, there are number of things you need to consider in order to ensure the successful conduct of a study. While we can’t predict the outcome, planning ahead for appropriate site conducting clinical studies in pediatric patient populationsand subject selection will take you one step closer. From study design to logistics to recruitment, there are real differences between studies conducted in pediatric populations and studies conducted in adult populations.

Patient Recruitment

While patient recruitment can be challenging in any study, there are additional challenges to recruiting pediatric patients.  Parents may be more risk averse to giving an unproven therapy to their child than they would towards receiving it themselves.  To improve the chances of successfully enrolling a study, it is important to consider potential motivators for participation:

  • Therapeutic benefit: If you are working on a therapy for a rare disease or for an indication where there is no approved or effective product, parents may be motivated by the opportunity to receive treatment that could improve their child’s condition even if it isn’t proven and if there is a chance they will receive placebo.  When there is an approved effective treatment available parents are likely to be reluctant to sign their child up when they may receive placebo, receive a treatment whose effectiveness is unknown, or receive a treatment with unknown side effects and safety issues.
  • Financial incentives: Many studies offer financial incentives to participants, and this can be a motivating factor for some parents.  Additionally, patients may receive study related medications, assessments, or more routine care that could be cost prohibitive otherwise.
  • Research benefit: Particularly for studies in rare disease or orphan indications, parents may see the benefit in research that provides a better understanding of the disease or the prospect of better treatment options in the future even if their child does not receive a direct benefit in participation.

Understanding what motivates parents to allow their child to participate in a clinical research study will help you to determine how to advertise and recruit for your study.  Some recruitment tactics (with appropriate ethics committee approval) to consider include:

  • Directly reaching out to parents by calling or through email.
  • Advertising at family events or locations where children and parents are likely to attend.
  • Reaching out to healthcare providers who may be the patients’ first point of contact even if they are not the location where the study will be conducted.  For example, if you conduct a study where the sites and investigators are typically at specialty practices, you may still want to recruit through primary care providers.
  • Consider referral processes for these types of sites to ensure patients are considered in a timely manner, based on their indication/treatment needs.

Patient Retention

using electronic devices in pediatric clinical studiesGetting pediatric patients enrolled in a study is great, but it is just as important to make sure most patients are completing the study.  There are a number of factors that make this more difficult in a pediatric study:

  • Multiple schedules to coordinate: Each study visit requires both the parent and child to be available.  Studies with numerous visits can become a significant hassle for parents, which can lead to discontinuations.  Making sure that every visit is necessary and being as accommodating as possible with scheduling, such as including flexible visit windows can mitigate this risk. (Remember: Most of the parents still have to work and kids attend school).
  • Parents don’t see the therapeutic benefit: If parents come to believe that their child is receiving placebo or that the treatment is ineffective, they may withdraw their child from the study. Providing clear information about what the trial is evaluating and encouraging frequent communication will help facilitate the parent voicing any concerns.
  • Discomfort of participation: No one likes long doctor visits or being stuck repeatedly with a needle, but these discomforts are even harder on pediatric patients and their parents.  Evaluate each assessment carefully during protocol development (even ones like blood pressure and temperature monitoring) to reduce the overall burden to the patient.

What can be done to improve retention? Encourage investigators to talk with parents about the importance of completing the study.  Consider what incentives may be appropriate to improve retention and work within the limitations of what the IRB will allow based on your study. Cash incentives may be effective with older patients and with parents.  In some cases, we’ve seen where study information or assessments are loaded on a device like a tablet that the patient may get to keep at the end of the study.  Treats or fun activities such as coloring books or video games to play at study visits can be good incentives for younger patients.  Keep in mind that there may be limitations on what you can provide as incentives.  All incentives will require IRB approval. Finally, keep visits as short as possible, limit blood draws and invasive procedures, that every procedure and assessment is truly necessary to determine the safety or efficacy of the investigational product.

Informed Consent

Pediatric studies introduce several challenges when it comes to informed consent:

  • Typically, if patients are at least 7 years old, in addition to parental consent you will need assent from the patient.  Assent documents will need to be written at an appropriate reading level.
  • In pediatric studies, parents are likely to want to know which treatment their child received and the outcome of the study after the study is complete.  Information on whether this will be made available needs to be included in the consent document.
  • You will need to decide whether consent is required from both parents.  If not, and the parents are divorced, can either parent make the decision?  If you do need consent from both parents, this can be an additional hurdle to enrollment.

Other Considerations

In our experience there are a number of other considerations that require proper planning to ensure study success:

  • Pregnancy tests: In many cases, pregnancy tests will be needed for female patients.  Depending on the age of the child and the view of the parents, this may be a hurdle.  In many cases, these tests are required at an earlier age than parents anticipate—typically as young as 9 years old.  Parents and patients do need to be informed if the test is being done.
  • Objective outcomes: For studies with young patients, objective outcomes are highly preferable to outcomes that rely on the reporting of the patient or parent.  If patient-reported scales are used, staff will need to be trained to get answers from the patient rather than the parent.
  • Sibling bias: The protocol will need to specify whether siblings can participate in the study.  Allowing siblings to participate may be helpful for enrollment, but it can also introduce bias into the results and potentially create a risk if home treatment is required.  There is a risk that if siblings are in different treatment arms, the treatments could be mixed up, while at home,  resulting in subjects receiving the incorrect treatment.
  • Dosing during school hours: If the protocol requires dosing during school hours, this may require extra paperwork/legwork on the part of the parent to gather supportive information allowing the school staff to give this investigational product (IP).  Many schools will not give IP to students and may not allow students to retain IP even if it is self-administered.
  • Missed school: Frequent visits during the school day or overnight visits may cause absenteeism issues for school-aged children.
  • Continuation: Consider whether participants will be able to continue receiving the product after the study, for example, through an open label extension of the study.  Even for a Phase III study, it may be several years before a product receives marketing approval.

Conducting clinical research in pediatric populations does introduce a unique set of challenges.  With proper planning, however, many of these challenges can be avoided or mitigated.

Download 5 Lessons Learned Conducting ADHD Trials

FDA Guidance on Non-Inferiority Clinical Trials to Establish Effectiveness

Posted by Brook White on Thu, Apr 20, 2017 @ 11:42 AM
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Heather Kopetskie, Senior BiostatisticianHeather Kopetskie, MS, is a Senior Biostatistician at Rho. She has over 10 years of experience in statistical planning, analysis, and reporting for Phase 1, 2 and 3 clinical trials and observational studies. Her research experience includes over 8 years focusing on solid organ and cell transplantation through work on the Immune Tolerance Network (ITN) and Clinical Trials in Organ Transplantation (CTOT) project.  In addition, Heather serves as Rho’s biostatistics operational service leader, an internal expert sharing biostatistical industry trends, best practices, processes and training.

In November 2016, the FDA released final guidance  on Non-Inferiority Clinical Trials to Establish Effectiveness providing researchers guidance on when to use non-inferiority trials to demonstrate effectiveness along with how to choose the non-inferiority margin, test the non-inferiority hypothesis, and provide interpretable results. The guidance does not provide recommendations for how to evaluate the safety of a drug using a non-inferiority trial design. This article provides background on a non-inferiority trial design along with assumptions and advantages and disadvantages of the trial design.

Background

A non-inferiority trial is used to demonstrate a test drug is not clinically worse than an active treatment (active control) by more than a pre-specified margin (non-inferiority margin). There is no placebo arm in non-inferiority trials. A non-inferiority trial design is chosen when using a placebo arm would not be ethical because an available treatment provides an important benefit, especially for irreversible conditions (e.g. death). Without a placebo arm to compare either the test or active control against it is important to determine that the active control had its expected effect in the non-inferiority trial. If the active control had no effect in the non-inferiority trial it would not provide evidence that the test drug was effective.
The table below compares superiority with non-inferiority trials with respect to the objective and hypotheses. The effect of the test drug is ‘T’ and the effect of the active control is ‘C’. The difference tested during analyses is C – T.

  Superiority Trial Non-inferiority Trial
Objective To determine if one intervention is superior to another To determine if a test drug is not inferior to an active control intervention, by a preset margin
Null Hypothesis No difference between the two interventions The test drug (T) is inferior to the active control (C) by some margin (M) or more (C – T >= M).
Alternative Hypothesis One intervention is superior to the other The test drug (T) is inferior to the active control (C) by less than M (C-T < M)

 

Selecting a non-inferiority margin in a trial is challenging but also critical to a successful trial. The largest possible choice for the non-inferiority margin is the entire known effect of the active control compared to placebo, called M1. However, doing this, would lead to a finding that the test drug has an effect greater than 0. More generally, the non-inferiority margin is set to some portion of M1, called M¬2, to preserve some effect of the control drug, based on clinical judgment. For example, if a superiority trial of the active control demonstrated to be 15% better than placebo, a clinician may set the non-inferiority margin to be 9% (M1=15%, M2=9%). This would be 6% worse than the active treatment, but still 9% better than placebo.

Multiple results are possible in a non-inferiority trial as explained in the graphic below. The point estimate is indicated by the square and is the measure of C – T; the bars represent a 95% confidence interval; and ∆ is the non-inferiority margin.

non-inferiority drug trial, interpretation of results

  1. Point estimate favors test drug and both superiority and non-inferiority are demonstrated.
  2. Point estimate is 0 suggesting equal effect of active control and active treatment. The upper bound of the 95% confidence interval is below the non-inferiority margin so non-inferiority is demonstrated.
  3. The point estimate favors the active control. The upper bound of the 95% confidence interval is less than the non-inferiority margin, demonstrating non-inferiority. However, the point estimate is above zero indicating that active treatment is not as good as the active control (C – T > 0), even while meeting the non-inferiority standard.
  4. Point estimate is 0 suggesting equal effect, but the upper bound of the 95% confidence interval is greater than the non-inferiority margin so non-inferiority is not demonstrated.
  5. Point estimate favors the active control and the entire confidence interval is above the non-inferiority margin so inferiority is demonstrated.

Non-inferiority Margin

The selection of the non-inferiority margin is critical in designing a non-inferiority trial and the majority of the FDA guidance focuses on this. The non-inferiority margin is selected by reviewing historical trials of the active control. The active control must be a well-established intervention with at least one superiority trial establishing benefit over placebo. If approval of the active control was based on a single study (not unusual in the setting of risk reduction of major events such as death, stroke, and heart attack), changes in practice should be evaluated. Using the lower bound of the 95% confidence interval provides a conservative estimate of the active control effect. If multiple historical trials exist one of the assumptions of the non-inferiority trial is consistency of the effect between the historical studies and the non-inferiority trial. Therefore, if consistency isn’t present between the historical studies this can lead to problems in estimating the active control effect. Inconsistency can also sometimes lead researchers away from performing a non-inferiority trial, especially if a historical trial did not demonstrate an effect. In situations with multiple historical trials, careful review of all study results and a robust meta-analysis are crucial to selecting an appropriate non-inferiority margin.

Assay Sensitivity and Constancy Assumption

Assay sensitivity is essential to non-inferiority trials as it demonstrates that had the study included a placebo arm, the active control – placebo difference would have been at least M1. The guidance outlines three considerations when determining if a trial has assay sensitivity.

  1. Historical evidence of sensitivity to drug effects
  2. The similarity of the new non-inferiority trial to the historical trials (the constancy assumption)
  3. The quality of the new trial (ruling out defects that would tend to minimize differences between treatments)

The constancy assumption in #2 above is that the non-inferiority study is sufficiently similar to the past studies with respect to the following design features.

  • The characteristics of the patient population
  • Important concomitant medications
  • Definitions and ascertainment of study endpoints
  • Dose of active control
  • Entry criteria
  • Analytic approaches

The presence of constancy is important to evaluate. For example, if a disease definition has changed over time or the methodology used in the historical trial is outdated the constancy assumption may be violated and the use of a non-inferiority design may not be appropriate. If all the design features are similar except the patient characteristics the estimate of the size of the control effect can be adjusted if the effect size is known in the patient sub-groups.

Benefits of non-inferiority trials

  • A non-inferiority trial is useful when a placebo controlled trial is not appropriate.
  • A non-inferiority trial may also test for superiority without concern about inflating the Type I error rate with care planning of the order in which hypothesis are tested. The reverse is not true; a superiority trial cannot claim non-inferiority.

Disadvantages of non-inferiority trials

  • Must be able to demonstrate assay sensitivity and the constancy assumption hold. This is especially difficult when medical practice has changed since the superiority trial (e.g. the active control is always used with additional drugs currently).
  • When the active treatment is not well established or historical trials have shown inconsistent results choosing a non-inferiority margin proves to be difficult.
  • If the treatment effect of the active control is small, the sample size required for a non-inferiority study may not be feasible
Download: Understanding Dose Finding Studies

The Rise of Electronic Clinical Outcome Assessments (eCOAs) in the Age of Patient Centricity

Posted by Brook White on Tue, Dec 06, 2016 @ 10:36 AM
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Lauren Neighbours, Clinical Research ScientistLauren Neighbours is a Research Scientist at Rho. She leads cross-functional project teams for clinical operations and regulatory submission programs and has over ten years of scientific writing and editing experience. Lauren has served as a project manager and lead author for multiple clinical studies across a range of therapeutic areas that use patient- and clinician-reported outcome assessments, and she worked with a company to develop a patient-reported outcome instrument evaluation package for a novel electronic clinical outcome assessment (eCOA).

Jeff Abolafia, Chief Strategist Data StandardsJeff Abolafia is a Chief Strategist for Data Standards at Rho and has been involved in clinical research for over thirty years. He is responsible for setting strategic direction and overseeing data management, data standards, data governance, and data exchange for Rho’s federal and commercial divisions. In this role, Jeff is responsible for data collection systems, data management personnel, developing corporate data standards and governance, and developing systems to ensure that data flows efficiently from study start-up to submission or publication. Jeff has also developed systems for managing, organizing, and integrating both data and metadata for submission to the FDA and other regulatory authorities.

patient centricityWith the industry-wide push towards patient-centricity, electronic clinical outcome assessments (eCOAs) have become a more widely used strategy to streamline patient data collection, provide real-time access to data (for review and monitoring), enhance patient engagement, and improve the integrity and accuracy of clinical studies.  These eCOAs are comprised of a variety of electronically captured assessments, including patient reported outcomes (PROs), clinician-reported and health-care professional assessments (ClinROs), observer reported outcomes (ObsROs), and patient performance outcomes administered by health-care professionals (PerfOs).  The main methods for collection of eCOA data include computers, smartphones, and tablets, as well as telephone systems.  While many companies have chosen to partner with eCOA vendors to provide these electronic devices for use in a clinical study, other sponsors are exploring “bring your own device (BYOD)” strategies to save costs and start-up time.  No matter what strategy is used to implement an eCOA for your clinical study, there are several factors to consider before embarking on this path.  

Designing a Study with eCOAs

The decision to incorporate an eCOA into your clinical study design is multifaceted and includes considerations such as the therapeutic area, the type of data being collected, and study design, but the choice can first be boiled down to 2 distinct concepts: 1) the need for clinical outcome data from an individual, and 2) the need for this data to be collected electronically. Thus, the benefits and challenges to eCOAs can be aligned with either or both of these concepts.

Regarding the first concept, the need for clinical outcome data should be driven by your study objectives and a cost-benefit analysis on the optimal data collection technique. Using eCOAs to collect data is undoubtedly more patient-centric than an objective measure such as body mass index (BMI), as calculated by weight and height measurements. The BMI calculation does not tell you anything about how the patient feels about their body image, or whether the use of a particular product impacts their feelings of self-worth. If the study objective is to understand the subjective impact of a product on the patient or health-care community, a well designed eCOA can be a valuable tool to capture this information. These data can tell you specific information about your product and help inform the labeling language that will be included in the package insert of your marketed product. Additionally, FDA has encouraged the use of PROs to capture certain data endpoints, such as pain intensity, from a patient population who can respond themselves (see eCOA Regulatory Considerations below). Of course, it’s important to note that the inherent subjectivity of eCOAs does come with its own disadvantages. The data is subject to more bias than other objective measures, so it’s critical to take steps to reduce bias as much as possible. Examples of ways to reduce bias include single- or double-blind trial designs, wherein the patient or assessor is not aware of the assigned treatment, and building in a control arm (e.g., placebo or active comparator) to compare eCOA outcome data across treatment groups.

Another important concept is the process for identifying and implementing the electronic modality for eCOA data collection.  Many studies still use paper methods to collect clinical outcome data, and there are cases when it may make more sense to achieve your study objectives through paper rather than electronic methods (e.g., Phase 1 studies with limited subjects).  However, several types of clinical outcome data can be collected more efficiently, at lower cost, and at higher quality with electronic approaches (e.g., diary data or daily pain scores).  From an efficiency standpoint, data can be entered directly into a device and integrated with the electronic data management system being used to maintain data collection balancing time and cost when considering paper or electronic clinical outcomes assessmentsfor the duration of the study.  This saves time (and cost) associated with site personnel printing, reviewing, interpreting, and/or transcribing data collected on paper into the electronic data management system, and it also requires less monitoring time to review and remediate data.  Additionally, paper data is often “dirty” data, with missing or incorrectly recorded data in the paper version, followed by missing or incorrectly recorded data entered into the data management system.  The eCOA allows for an almost instantaneous transfer of data that saves the upfront data entry time but also saves time and cost down the road as it reduces the effort required to address queries associated with the eCOA data.  Aside from efficiencies, eCOA methods allow for more effective patient compliance measures to be implemented in the study.  The eCOA device can be configured to require daily or weekly data entry and real-time review by site personnel prior to the next scheduled clinic visit.  Additionally, the eCOA system can send out alerts and reminders to patients (to ensure data is entered in a timely manner) and to health-care personnel (to ensure timely review and verification of data and subsequent follow-up with patients as needed).  The downsides to electronic data collection methods tend to be associated with the costs and time to implement the system at the beginning of the study.  It’s therefore essential to select an appropriate eCOA vendor  early who will work with you to design, validate, and implement the clinical assessment specifically for your study.

eCOA Regulatory Considerations

In line with the industry push for patient-focused clinical studies, recent regulatory agency guidance has encouraged the use of eCOAs to evaluate clinical outcome data.  The fifth authorization of the Prescription Drug User Fee Act (PDUFA V), which was enacted in 2012 as part of the Food and Drug Administration Safety and Innovation Act (FDASIA), included a commitment by the FDA to more systematically obtain patient input on certain diseases and their treatments.  In so doing, PDUFA V supports the use of PRO endpoints to collect data directly from the patients who participate in clinical studies but also as a way to actively engage patients in their treatment.  The 2009 FDA guidance for industry on Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims , further underscores this idea by stating “[the use] of a PRO instrument is advised when measuring a concept best known by the patient or best measured from the patient perspective.”  The 2013 Guidance for Industry on Electronic Source Data in Clinical Investigations  provides the Agency’s recommendations on “the capture, review, and retention of electronic source data” and is to be used in conjunction with the 2007 guidance on Computerized Systems Used in Clinical Investigations for all electronic data and systems used in FDA-regulated clinical studies, including eCOAs.  To support these efforts, the FDA has developed an extensive Clinical Outcome Assessment Qualification Program, which is designed to review and assess the design, validity, and reliability of a COA for  a particular use in a clinical study.  Furthermore, the newly formed Clinical Outcome Assessment Compendium  is a collated list of COAs that have been identified for particular uses in clinical studies.  The COA Compendium is further evidence of FDA’s commitment to patient-centric product development, and it provides a helpful starting point for companies looking to integrate these assessments into their clinical development programs. 

Before choosing an eCOA for your clinical development program, the following regulatory factors should be considered:

  • FDA holds COAs to the same regulatory and scientific standards as other measures used in clinical trials. Thus, it is advisable to refer to the Guidance for Industry on Patient-Reported Outcomes and the available information on the COA Assessment Qualification program and COA Compendium provided by the Agency when implementing eCOAs into your development program. If you plan to divert from currently available regulatory guidance, make sure to have a solid rationale and supporting documentation to substantiate your position.
  • The qualification of an eCOA often requires input from patients and/or health-care professionals to evaluate the effectiveness of the assessment. This input is necessary for the regulatory agency to determine whether the eCOA can accurately measure what it’s supposed to measure (validity) and to demonstrate it can measure the outcome dependably (reliability).
  • Data collected from qualified and validated eCOAs can be used to support product labeling claims. The key is to use an eCOA when it’s appropriate to do so and to make sure the eCOA supports your intended labeling claims because the instrument will be evaluated in relation to the intended use in the targeted patient population.
  • For the cases where an instrument was developed for paper based collection or an instrument is collected using multiple modes, it may be necessary to test for equivalence. This regulatory expectation is often required (especially for primary and secondary endpoints) to ensure that the electronic version of the instrument is still valid and data collected with mixed modes are comparable.

A CRO Can Help with your eCOA Strategy

CROs partner with sponsor companies to develop and execute their product development strategies.  In some cases, this involves implementing clinical outcome measures into a development program and then facilitating the interactions between the company and regulatory authorities to ensure adequate qualification of the COA prior to marketing application submission.  Whether or not you choose to engage a CRO in your development plan, consider seeking outside consultation from the experts prior to establishing your eCOA strategy to give you and your company the best chance of success.  

CROs Can Help:

  • Determine endpoints where eCOA data is appropriate
  • Determine the cost/benefit of electronic vs paper data capture
  • Determine the best mode of electronic data capture
  • Recommend eCOA vendors when appropriate
  • Perform equivalence analysis
  • Facilitate discussions with regulatory authorities
  • Manage the entire process of eCOA implementation

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Craftsmanship in Clinical Trial Study Design

Posted by Brook White on Wed, Jul 06, 2016 @ 02:55 PM
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Ryan Bailey, Senior Clinical ResearcherRyan Bailey, MA is a Senior Clinical Researcher at Rho.  He has over 10 years of experience conducting multicenter asthma research studies, including the Inner City Asthma Consortium (ICAC) and the Community Healthcare for Asthma Management and Prevention of Symptoms (CHAMPS) project. Ryan also coordinates Rho’s Center for Applied Data Visualization, which develops novel data visualizations and statistical graphics for use in clinical trials.

Shann Williams, Senior Director OperationsShann Williams has 10 years of experience managing clinical trials. She is a Sr. Director of Operations and the program director of the statistical and clinical coordinating center of the Transplantation Group for the division-wide consolidated coordinating center sponsored by the National Institute of Allergy and Infectious Disease (NIAID).  In addition, Shann serves as Rho's project management operational service leader, an internal expert sharing project management best practices, processes and training.

My dad is an expert carpenter and handyman. Growing up, I spent hours watching him work - furniture, flooring, painting, plumbing, roofs, siding, decks - you name it, he did it. I learned a lot from watching him and helping him, but I never accomplished his level of expertise and proficiency. It is not for lack of knowledge or ability; rather, it is a lack of practice and experience. I'm capable. My father is masterful.

craftsmanship in clinical trial study designClinical trials are not so different from construction and craftsmanship. To be a successful clinical researcher, you need to coalesce expertise across a variety of domains - statistics, data management, project management, clinical operations, product safety, regulatory, medical writing - as you design, prepare, execute, and troubleshoot throughout the trial. The CRO industry exists because we provide specialty expertise in these areas, and many pharmaceutical companies are glad to have a trusted partner to manage various aspects of this work.

Yet, regardless of which CRO services pharmaceutical companies seek out, one task pharmaceutical companies have been reluctant to source to their CRO partners is clinical trial design. According to a recent press release by Cutting Edge Information, as recently as 2014, no Top 50 pharmaceutical or medical device team surveyed reported that they shared clinical trial design responsibilities with CROs.

This is not especially surprising. With their product on the line, pharmaceutical companies have a keen interest in retaining careful control over the study design. It is also a matter of practicality. Before seeking out a CRO to support management of your trial, it helps to have a well-constructed plan of how the trial should be executed. However, Cutting Edge Information reports that this trend is likely to change dramatically in coming years. By 2020, over 50% of companies they surveyed plan to share trial design responsibilities with CROs. Why the change?

In part, it's due to the need for craftsmanship. When it comes to clinical trials, CROs offer a level of end-to-end proficiency built on decades of extensive trial management experience and specialization. When your job is conducting hundreds of trials for a wide range of clients and diverse therapeutic areas, you naturally achieve a high degree of expertise: a deep knowledge base, valuable foresight, honed skills, improved efficiencies, and the ability to operate deftly in a complex and highly regulated environment. As the ones most often implementing the trials, overseeing the day-to-day project operations, and conducting analyses, CROs are in the best position to identify the strengths and weaknesses of clinical trial designs.

With the pace of new drug and device development lagging, costs increasing, and pressure to get efficacious products to market building, clinical trial designs have come under growing scrutiny. Bad blue prints lead to less than optimal functionality or worse: a complete do-over. In the same way, even simple trial design errors will lead to less than optimal results. The need for a do-over can be cost-prohibitive or just plain disastrous.

By incorporating CROs in the design process, pharmaceutical companies will foster closer partnerships, reduce costs by leveraging efficiencies, benefit from the extensive experience CROs have to offer, and craft more effective trials. Independently, pharmaceutical companies and CROs are capable. Together, we are masterful.

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Working In Vulnerable Patient Populations: Research in the Cognitively Impaired

Posted by Brook White on Wed, May 25, 2016 @ 11:07 AM
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research in dementia, cognitively impairedResearch involving cognitively impaired patients requires researchers to take extra precautions to protect these patients. There are a number of reasons a patient may be considered cognitively impaired—psychiatric illness, a medical or neurological disorder which may temporarily impair decision making , and dementia to name a few. According to the New York Times, the population of Americans over the age of 65 will nearly double by the middle of the century—a trend which has been referred to as the graying of America. With an increasingly elderly population, more potential research subjects will suffer from various forms of cognitive impairment and there will be a greater demand for treatments for age-related conditions. The likely result is the need to incorporate larger numbers of cognitively impaired patients in research studies.

As researchers, we need to consider how we simultaneously protect patients who are cognitively impaired or may become cognitively impaired during a study with the need to include this population as part of our research. Unlike children, pregnant women, and prisoners, the current Code of Federal Regulations for the Protection of Human Subjects (45 CFR Part 46) does not contain specific guidance for the protection of subjects with cognitive impairment in clinical trials.

Informed Consent

One key issue related to cognitively impaired subjects is informed consent.  Many of the items discussed here are related to consent.  If a research subject has substantial cognitive impairment, they cannot provide informed consent.  In this case, a legally authorized representative (LAR) must provide consent on their behalf.  The standard for an LAR to provide consent is substituted judgment—what is in the best interest of the subject and what would the subject want.  If possible, the subject should assent.  In situations where a subject refuses to provide assent, the subject should generally not be included in the study.

Deciding if a Patient is Cognitively Impaired

Dementia is often a matter of degree, and in mild forms of cognitive impairment, a patient may still be capable of providing consent.  How do we decide when a patient is competent to consent and when an LAR is needed?  This certainly isn’t a settled matter, but one option is to include an assessment which would be performed by the investigator as part of the screening process to make this determination.  The assessment should check the patients understanding of potential risks, potential benefits, that participation is voluntary, and what will be involved in participating (study procedures, additional visits). 

Consent is a Process, Not a One Time Event

In many cases involving dementia, a patient’s decision making ability may degrade over the course of a study.  It may be that a patient is capable of providing informed consent at the beginning of a study, but is not as the study progresses.  This is something investigators should keep in mind.  You may want to plan for reassessment later in the study.

Identifying LARs

There is not a single standard for determining who can act as an LAR.  Some states have enacted laws specifying who can act as LAR, but the laws are not all the same.  In states where there isn’t a law, identifying an LAR can be trickier.  In other countries and cultures, views on who can make decisions for the cognitively impaired vary greatly from common views in the US.  Make sure at the start of the trial that you are aware of local laws and standards related to LARs.

Limiting Risk

Study designs should take extra care in limiting risk exposure in studies which will be using cognitively impaired patients, particularly when there is little or no potential for direct benefit. In most cases, studies involving these patients that don’t offer the potential of direct benefit should be limited to those involving minimal risk.

In conclusion, because formal guidance on conducting clinical research in subjects with cognitive impairment has not yet been standardized or incorporated into law, it is important to take extra care to protect these patients. We’d be interested in knowing how other organizations are responding to this issue. Is this a topic your organization is actively addressing? If so, please share in the comments.

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5 Tips for Conducting Feasibility for a New Clinical Trial

Posted by Brook White on Wed, Apr 20, 2016 @ 02:12 PM
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Meagan Vaughn, PhD, Research ScientistMeagan Vaughn, Ph.D., Research Scientist,  designs and implements clinical trial feasibility assessments.  She has over 10 years of experience in scientific writing and editing, has authored and contributed to numerous peer-reviewed publications, and serves as a reviewer for several medical and public health journals.  

What does the word “feasibility” mean to you? It may seem like a simple question, but I have found that “feasibility” has many interpretations within the clinical research industry. When we work with a sponsor to conduct feasibility for clinical trial planning, our first task is to figure out what their definition of feasibility is, and more specifically, what questions they are trying to answer.

Most often, the question is “How many sites will we need to meet our enrollment target and timelines for this study?” Of course, this is an important question, but asking this question can be putting the cart before the horse. The foundation of a successful study is a protocol that is both scientifically sound and viable from an operational perspective. Assuming the former has been sufficiently vetted, the first goal of conducting feasibility should be to test the assumptions of the latter. This is the time to think through the logistics for the site and the subject, and consider the protocol requirements that might affect factors like enrollment, retention, and data quality. Use this exercise to formulate questions that will stimulate a dialogue around these issues with potential investigators. For this type of early stage feasibility, you also need to think about the right tool to gather the information needed, and a web-based survey probably isn’t going to cut it if you are looking for thoughtful feedback. This is the time to leverage relationships with investigators and coordinators to have some focused conversations using your questions as a guide for the discussion. More often than not, they will be able to quickly identify potential show stoppers in your inclusion/exclusion criteria, as well as assessments or design elements likely to result in frequent protocol deviations.

Once the feasibility of the protocol has been thoroughly evaluated, the next step is to examine the feasibility of the trial given the constraints of timelines and resources. To this end, a web-based survey can be a quick way to gather data to inform enrollment projections and come up with a list of candidate sites. Below are a few points to consider when crafting a feasibility questionnaire:

  • Asking the right questions is just as important as not asking unnecessary questions.   Stay focused on the key pieces of information needed.  If you aren’t going to analyze it, don’t ask the question.
  • A poorly written question will result in unreliable data.   Consider your audience and have several people review and test the survey before deploying.   For example, consider the question “How long does study startup typically take at your site?”  Without defining the starting point (receipt of the protocol, site selected, or receipt of the regulatory packet), the answers may vary widely.
  • Judicious use of skip logic and display logic in an electronic questionnaire can reduce the burden on respondents and provide cleaner data to the person on the receiving end.   For example, you can use skip or display logic to drill down into specific topics that may only be relevant for some sites (such as regulatory history for sites that have had an inspection).
  • Engage sites in the feasibility process by asking questions requiring their input (e.g., any question that starts with “In your experience…”).
  • Use the right tool to collect information.  At Rho, we use Qualtrics as a survey platform. This platform provides many advantages for conducting feasibility, including:
    • Responsive surveys (skip logic, display logic, survey branching),
    • Piped text (automatically fills in certain fields for sites that have responded to previous surveys), and
    • Real-time reports that can be published to the web for sponsor review

One strategy that we have found to be successful in helping sponsors meet timelines for study startup is to start feasibility and site identification activities under a consulting agreement during the RFP/bid-defense/contracting process. Once a CRO partner has been selected, the team can hit the ground running with site startup activities. This type of early feasibility effort can also facilitate protocol development by gathering site feedback on key operational parameters.

The take home message for feasibility? Spend a little time thinking critically about the key pieces of information that you need that are unique to your project and goals. This will help to hone your feasibility strategy so that you can ask the right questions using the most effective approach.

Protocol Design and Development Webinar: Follow-up Q&A

Posted by Brook White on Thu, Feb 04, 2016 @ 11:07 AM
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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.  

Watch Webinar

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.

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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?

Rho provides protocol design and development services. You can learn more on our website or by contacting us.

Check out our other on-demand and upcoming webinars here.

David Shoemaker, SVP R&DDavid 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-1.jpgKaren 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.

Q&A: Using ePRO with Smart Devices

Posted by Brook White on Fri, Jul 17, 2015 @ 10:58 AM
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Emily Cantrell, Senior Director OperationsBecky Baggett, Senior Project ManagerEmily Cantrell, Senior Director Operations, and Becky Baggett, Senior Project Manager recently completed enrollment six weeks early on a phase 3 study using ePRO with a tablet.

On June 10th, we hosted a webinar featuring a case study using ePRO with a smart device. If you missed the webinar, you can click here to register and view the webinar on-demand.

Several questions came up during the webinar that we did not have time to address. Below, we’ve responded to the unanswered questions that were submitted during the webinar.

Q: You mentioned that the guidance on Equivalence Validation is vague and your decision to include was a conservative approach due to the trial being a Phase III pivotal. Can you provide additional comment on when EV will and will not be required?

A: It is difficult to say when this equivalence validation should or should not be performed; however, the impact of the data collected for your marketing claims may help you decide. In our case, since our primary efficacy endpoint for our pivotal phase III was captured on the tablet, the Sponsor and Rho felt it was an important step in support of the data validity. At the time this was a very expensive decision, but it may be the case that the vendor has PROs in their library that have previously been validated, perhaps reducing the impact of cost on your decision.

Q: Are you aware of any tablets that utilize thumb print technology in lieu of a subject PIN?

A: We did not use this technology for our study nor have we been presented with this technology from our vendors.

Q: Can you comment on smart phone apps and other methods for patients to do ePRO at home?

A: Rho does have experience working with a vendor that issues smart phones as at-home devices. The challenges here are ensuring the subjects keep the batteries charged, take care of the device and remember to enter their outcomes. To date, Rho does not have experience using a smart phone application, but we are exploring this option. We have learned that many of the challenges one would experience with the average smart phone technology may complicate the use in clinical trials as well. For example, subjects may inadvertently delete the app from their phone, operation system upgrades may change the way the app interacts with the user, or subjects may lose or damage their phone. One other point of consideration is how subjects may be compensated for the use of their data plan.

Q: Does validation have to be specific to the exact device such as an iPad vs a smart phone app vs another tablet type?

A: In our case, we utilized the exact device with the validation subjects to ensure they were reviewing exactly what the study subjects would be using. For studies that have VAS outcomes, Rho would strongly recommend using the exact device to ensure that the size and scaling did not impact the outcome. For NRS or simple questionnaires, it’s not as pressing, but Rho would recommend obtaining the vendor's prior experience interacting with the FDA to inform the decision.

Q: Do you have experience using an app vs a separate device?

A: To date, we have not yet had experience with using an app versus a device. We realize there may be challenges for this and would want to carefully weigh the options with the Sponsor and study team during study start-up.

Q: How is the translation vendor selected? Does Rho typically select the translation vendor, or do you leave that up to the sponsor or ePRO vendor?

A: Rho has preferred providers for translation, and we do a cost comparison for each bid. There are times where the vendor has been selected by the Sponsor, so we will use their vendor.

Free Webinar: Selecting Inclusion/Exclusion Criteria for Your Next Trial

Addressing Diversity in Clinical Trials

Posted by Brook White on Mon, Nov 24, 2014 @ 09:55 AM
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Shann Williams, Clinical Trials in Transplantation Project DirectorShann Williams is the Project Director of the statistical and clinical coordinating center for the Clinical Trials in Transplantation (CTOT) program sponsored by the National Institute of Allergy and Infectious Disease (NIAID).  In addition, Shann serves as Rho's project management operational service leader, an internal expert overseeing project management processes and training.

Michelle Walter, AVP OperationsMichelle Walter, AVP Operations, has considerable experience directing federally-funded respiratory and allergy clinical research. Her background as a project director of multi-protocol, multi-site clinical programs has been a considerable asset over the course of her fifteen year tenure at Rho.  For the last 8 years, she has been the project director for the Statistical and Clinical Coordinating Center for the Inner City Asthma Consortium, an NIAID-funded network of clinical and mechanistic sites. 

diverse patient/subject populations in clinical trialsA recently released Food and Drug Administration (FDA) report encourages enrollment of more women and minorities in clinical trials. The report identifies three priorities in order to address this need: participation, data quality, and transparency. Clinical research organizations (CROs) can help guide sponsors in all of these areas in order to ensure that their drug and device applications not only meet all of the current requirements, but that they are at the forefront of the direction of the FDA and of biomedical research as a whole.

Overcoming Barriers to Participation:

Finding solutions to barriers that limit participation in clinical trials by demographic subpopulations, particularly those populations that are underserved and underrepresented, is key to diversifying enrollment.

There are several ways sponsors and sites can overcome these barriers. Using available census data, mapping technologies, and peer-reviewed publications to understand the demographic variability of the disease population by region, site-specific enrollment goals and strategies can be created to ensure that percentages of subjects targeted and enrolled accurately reflect the available subpopulation at that site. Similarly, selecting new sites whose community make-up will help achieve enrollment goals can help if other sites encounter limitations.

hurdles to participation in clinical trialsAddressing the needs of non-native English speakers in the United States is immensely important to encouraging diversity. Sponsors can develop appropriate recruitment materials using the subpopulation’s native language and ensure these materials are accessible to the population of interest. Translation services and on-site translators also aid in ensuring informed consent forms are easily understood and thoroughly explained. Choosing translators with the same demographic background as subjects under study helps dispel mistrust and miscommunication. It is also important to administer informed consent forms in a format that is acceptable in that subpopulation. For example, providing adequate time and resources for all applicable family members to review information and offer guidance to the participant about whether or not they should consent may increase enrollment and help reduce drop out during the trial.

Identifying and addressing the motivations, cultural preferences and common barriers to participation for various sub-populations may increase recruitment and retention. Providing solutions to sites to address these barriers – including: tools and training for literacy problems, transportation or reimbursement for transportation, childcare options, flexible visit schedules to help with variable work schedules and options other than checks for participation reimbursements – all help to improve recruitment and retention and diversify enrollment.

Ensuring Data Quality:

As noted in the FDA report, data standards are integral to improving the completeness and quality of information based on demographic subgroups. Identify a CRO partner that has demonstrated leadership in the development and application of data standards. For example, it is important to have subject matter experts that have worked closely with the FDA and its reviewers on numerous clinical development programs, with a track record of successful submissions of several marketing applications with extensive demographic subgroup analyses.

Free Webinar on Cost Effective Data Standards 

 

 

Transparency in Reporting:

transparency in clinical trialsData transparency must be a seamless next step in the clinical trials process, both for submitting reports to the FDA and for informing trial participants of the outcomes. Although the FDA report specifically focuses on data transparency in reporting to the FDA and other data sharing venues, providing study results directly to the trial subjects and their families helps to reinforce that these subjects have personally contributed to research in the disease area that impacts them personally. Results can be presented in the form of newsletters, handouts and tailored materials specific to the subpopulation of interest. This type of transparency further strengthens positive feelings regarding biomedical research as a whole to combat cultural and historical mistrust.

 

Q&A: Clinical Trial Inclusion & Exclusion Criteria Webinar

Posted by Brook White on Fri, Sep 12, 2014 @ 11:27 AM
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questions about inclusion and exclusion criteriaOn September 9th, we hosted a webinar featuring Senior Medical Officer Jack Modell about improving inclusion and exclusion criteria for your next clinical trial.  If you missed the webinar, you can click here to register and view the webinar on-demand.

Several questions came up during the webinar that Dr. Modell did not have time to address.  Additionally, during one part of the webinar participants were asked to submit possible inclusion and exclusion criteria that could be used for a particular scenario, and there were a couple of submitted criteria he did not have time to discuss.  Below, Dr. Modell has responded to the unanswered questions and provided some insight on additional inclusion and exclusion criteria that were submitted during the webinar.

Q: How can you extrapolate your intended patient population between different phases of the trials?

A: Generally, as drug development progresses and more safety information is available, the population can be expanded accordingly.  Thus, phase I trials are usually limited to healthy controls, pivotal trials are generally in a broad target population for whom the drug will be indicated, and phase 4 (post-marketing) trials often extend to previously untested populations (e.g., patients with comorbidities, other target diseases, etc.), safety permitting.

Q: What about adaptive trials, with a number of target groups?

A:Adaptive trials are fine as long as they are appropriately designed with adequate power to detect effects of interest in each group (and the exisiting safety data base makes use in the different groups acceptable).  Cautious use beyond known safety is often appropriate (otherwise we couldn't test or progress new drugs at all); but as always, the potential risks vs. benefits for the research subjects and intended patient populations must be carefully assessed.

Q:Once a patient is in the study, and it is determined that the patient was entered in to the study despite not meeting one of the I / E criteria, do you immediately terminate the patient from the study if it is not a safety issue?

A: Yes, I would generally terminate because you are then studying a subject for whom the study wasn't approved and/or the drug wasn't intended.  These subjects should, however, generally be followed as long as necessary (usually as specified by the protocol) for safety assessments.  Of course, one might counter, "Well, what if the I/E criterion that the subject failed to meet wasn't really that consequential -- 'no big deal, really'?"  To that I would have to ask why an "inconsequential" I/E criterion was included in the first place (maybe shouldn't have been?), but of course that's academic at this point.  Nonetheless, I/E criterion really shouldn't be "second guessed" for subjects once the trial is underway (barring global reassessments and protocol amendments to deal with that), so I would still say that the subject should be discontinued from the study except for safety follow up.  

Q: Is it ethical for the PI to be a participant in the study?

A: Great question.  I'm not sure that it is necessarily "unethical," but the question is whether there's a good reason for the PI not to be a subject.  And for most studies, I think it would be inadvisable because the PI has a vested interest in the outcome and so it would be very difficult for him or her to be completely objective. He or she is hardly representative of the "random" populations that we usually need for drug development.  On the other hand, there may be circumstances, such as when risks are minimal and there is no way that the data can be affected by the PI's vested interest (e.g., a study of height, weight, or other information that is fixed and objective) where the PI's participation might be acceptable.  In any case, if the study is subject to IRB approval, as most are, the PI's involvement should be cleared with the IRB ahead of time.

Q: Many people - not only in EU - consume low to moderate levels of alcohol even during times when they are undergoing treatment. People with blood alcohol should not be excluded because it is reflective of the actual real world population. Any comment?

A: A good point.  But please note that I didn't suggest excluding any alcohol use at all, but rather, only those who could not commit to abstaining for 8 hours before screening and/or randomization (generally not too much to ask considering these 8 hours would usually be in the morning) and those whose BACs are above .015 when tested because this either means that they didn't abstain when they said they would (which raises a question of compliance) or that they had levels 8 hours previous that could only have been attained by very heavy drinking.  One of course could quibble with the ".015" (why not .010 or .020?), but the goal is to do your best to exclude those likely to be heavy drinkers, realizing that you'll lose a few who aren't, but this is generally better than over-including those who do have a problem.  As for the point of testing a drug in the "real world" population of heavy drinkers, if this is really the goal, a separate study (adequately powered and with appropriate precautions) would be a better way to do this.

Exlusion Criteria: Excessive user of depressant drugs such as alcohol - no more than 1 drink a day

Yes, this would be an appropriate exclusion criterion, although would need to be more specific about use of depressant drugs.  One drink a day is reasonable, especially since many subjects will underreport drinking.  

Exclusion Criteria: No history of pre-syncope / syncope. Normal potassium / magnesium. QTcF < 450 msec

Reasonable given that there may be a QTc concern.  

If you have additional questions about the webinar, please submit them in the comments below.  Also, feel free to share additional inclusion/exclusion criteria based on the scenario shared in the webinar.

About the Speaker:

Dr. Jack Modell, Rho Senior Medical OfficerJack Modell, M.D.
Senior Medical Officer 
Dr. Modell is a board-certified psychiatrist with 30 years of experience in clinical research, teaching, and patient care including 10 years of experience in clinical drug development (phases 2 through 4), medical affairs, successful NDA filings, medical governance, drug safety, compliance, and management in the pharmaceutical industry. His specialties and expertise include neuroscience, psychopharmacology, drug development, clinical research, medical governance, and clinical diagnosis and treatment. 

Dr. Modell has authored over 50 peer-reviewed publications in addiction medicine, anesthesiology, psychiatry, neurology, and nuclear medicine. He has lead several successful development programs in the neurosciences. Dr. Modell is a key opinion leader in the neurosciences, has served on numerous advisory and editorial boards, and is nationally known for leading the first successful development of preventative pharmacotherapy for the depressive episodes of seasonal affective disorder.

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