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Is a Target Product Profile Worth the Effort?

Posted by David Shoemaker on Wed, Dec 18, 2019 @ 09:32 AM


David Shoemaker, PhD, SVP R&D, has over 25 years of experience in pharmaceutical product development. He has served as a Program Leader or Advisor for multi-disciplinary program teams and has been involved with ensuring products meet regulatory standards at all stages of the development process.

A recent study by the MIT Sloan School of Management determined only 14 percent of clinical studies succeed, indicating there is room for vast improvement in the pharmaceutical industry’s ability to develop needed therapeutics more efficiently1. Inasmuch as the clinical develop program for a product comprises several to dozens of clinical studies to achieve marketing approval, chances are that one or more studies will fail during development. Coincidentally, this success rate of 14 percent approximates the age-old estimate that 10 to 20 percent of products that enter human studies make it to the market2,3. However, an eventual failure rate of 80 to 90 percent for products entering Phase 1 speaks to more than simply clinical study failure rate. The failure rate indicates an overall development process shortcoming that begins during the preclinical stage and destines product development programs for failure. This is due in part to the fact that companies are in many cases not doing the correct clinical study on an efficient path to marketing a needed therapeutic product. They do not possess a road map for success.

As a contract research organization who works extensively with late stage development companies collaborating on the preparation of their marketing applications, Rho continually observes product sponsors who fail during late stage development due to preventable missteps with their product development program. We are always buoyed by starting a new relationship with a company who has taken the time to prepare a Target Product Profile (TPP) because we know we have a client who understands the importance that prescribing information and market position play in the ultimate approval of a product by the regulatory authorities and the commensurate successful market capture. Simply achieving marketing approval is not the goal. The goal is to provide a useful therapy that will meet the needs of patients, physicians, and payers and hopefully advance current therapeutic options. The TPP provides a road map for development of a product, laying out all the key development performance criteria that the investigational product must meet in order to ultimately become the useful therapy the sponsor wants it to be; failure to meet any of these key criteria means the investigational product will not succeed as a useful marketed product and development should be abandoned or somehow re-engineered.

The crafting of a TPP is enabled by a detailed understanding of not only the disease and its associated market, but also unmet patient, physician and payer needs. The goal posts for each of the stakeholders need to be determined by identifying the minimal and the optimal characteristics for a variety of TPP elements. The major criteria to meet patients’ needs reside primarily in efficacy and safety elements, but satisfying dosage, route of administration, and specific patient reported outcomes also must be considered. Obviously physicians’ primary needs will be met if the patients are satisfied but there may be additional considerations regarding route of administration as well as ease and efficiency of therapy. Payer value is derived from beneficial differentiation of efficacy and safety but there may also be differential market forces to consider based on geographical regions (e.g., free market, US; clinical effectiveness, France and Germany; cost effectiveness, UK and Canada). If it becomes clear at any point in development that you will fail to meet the minimal criteria for your product to satisfy any one of these stakeholders’ regulatory or commercial requirements, a company is well advised to abandon development. Also, it is simply common sense for companies to Data analysis chart and graphs-2identify their principal competitive product on the market as well as potential competitive products in development prior beginning their development program in earnest. A comprehensive TPP should contain all of these elements.

The organization of the TPP is understandably varied across the industry with some people using the US Prescribing Information as a template and others adopting the European Summary of Product Characteristics. The FDA even issued guidance back in 2007 advocating the use of the US Prescribing Information organization (https://www.fda.gov/media/72566/download). The advantages of these strategies include the fact that you are effectively preparing your US annotated package insert during your development plan. These documents help both with minimizing and focusing development activities and organizing your marketing application, and they are in a format optimal for discussions with regulators. However, a complete TPP should still include an independent payer assessment that is of no interest to regulators. Other companies prefer more general categories than are found in product labeling such as efficacy, safety, payer value, dosage, indication, population and juxtapose these elements with the attributes of their target competitive product for a more commercially oriented TPP. This allows one to easily see when your product comes up short against a competitor thereby rendering a course correction or a No Go decision.

By focusing both the developmental and marketing goals in the TPP at the preclinical stage a company is able to build a commercial differentiation strategy into their early development plan. Preclinical studies are a lot less expensive to conduct than clinical studies and hypotheses can be tested versus competitive products efficiently. These preclinical experiments may or may not lead to earlier examination of active comparator studies in the clinic. However, it will most certainly enforce the understanding that validating a novel mechanism of action is less important than clinical differentiation from a competitive product. These experiments may allow a company to distinguish between competitors and identify the key competitive product to compete against. Demonstrating proof of concept in no way guarantees profit on return, so it is imperative that companies explore pharmacodynamic activity versus competitive products in their preclinical development programs.

A common reason small or inexperienced companies do not prepare a TPP is the proposed cost and amount of time that must be devoted to its preparation. Companies with an exit strategy at proof of concept or prior to phase 3 often claim the cost is not justifiable. However, the value created by a well-run development program that checks all the boxes for an intelligent investor is worth much more than the cost invested in the preparation of the TPP. Investment firms and big pharma are primarily looking for investments where the risks have been minimized and a program that has been conducted efficiently focusing on the ultimate appropriate indication and patient population while examining carefully the commercial landscape holds enormous value.

Perhaps the greatest value of the TPP is as a communication tool. The ultimate goal of the communications-networkdevelopment program is shared clearly and continually with all the company disciplines, e.g., clinical, preclinical, chemistry manufacturing and controls, regulatory, and marketing. The TPP is also able to be used as an external communication tool that facilitates interactions with regulatory authorities, investors, and the media. The document can be used to help structure regulatory and investor briefing documents as well as press releases. The TPP’s additional use as a communication tool is as an educational document for new team members whether they are within the company or at regulatory authorities.

The bottom line is, you must prepare a TPP early and revise it continually during development if you wish to bring a successful therapeutic to market to advance patient treatment or you are left relying on nothing more than good fortune.

1 Wong, C.H, Siah, K.W., and Lo, A.W. Biostatistics. 2019; 20(2): 273 – 286.
2 https://www.reuters.com/article/us-pharmaceuticals-success/success-rates-for-experimental-drugs-falls-study-idUSTRE71D2U920110214
3 https://www.policymed.com/2014/12/a-tough-road-cost-to-develop-one-new-drug-is-26-billion-approval-rate-for-drugs-entering-clinical-de.html


Orphan Drugs and Single Trials

Posted by Joseph Watson on Thu, Dec 12, 2019 @ 09:00 AM

Joseph Watson, PhD, RAC, Research Scientist at Rho, has experience in both regulatory submissions and clinical document preparation, with over fifteen years of experience in scientific writing and editing jwatsonclinical and nonclinical documents, including numerous publications in peer-reviewed journals.  Dr. Watson has led the preparation, review, and coordination of a variety of regulatory and clinical documents, including protocols; clinical study reports; integrated summaries of biopharmaceutics, safety, and efficacy; CMC and nonclinical documents; draft product labels; and 120‑day safety updates.  His writing and editing experience covers a broad range of therapeutic areas, including drug addiction, middle ear disorders, infectious diseases, psychiatric disorders, acute and chronic pain, multiple sclerosis, hemophilia, and oncology. 

Since the enactment of the Orphan Drug Act in 1983, the number of orphan drug approvals has risen steadily. In 2018 alone, 34 out of 59 approved novel medications were for orphan diseases. Consistent with the increase in orphan applications reviewed by the Agency, Rho has received an increasing number of sponsor requests for support of programs working towards an orphan drug approval. Our sponsors often think that their product can be approved with support from a single trial, but how realistic is this stance? To better understand when a single trial approval is possible, we look to FDA guidances.Conceptual image with ladder reaching increasing graph-1

In the 1998 Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, FDA spells out the potential circumstances in which a single clinical trial for a novel therapeutic could be sufficient to support an efficacy claim. The guidance states “reliance on only a single study will generally be limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity, or prevention of a disease with potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible.”

The key points outlined in the guidance are:

1.   The condition must be serious. If the FDA doesn’t believe the condition is serious, they will not consider a single adequate and well controlled trial for a novel therapy.
2.   A second adequate and well-controlled trial is practically or ethically impossible to conduct. This situation could apply for an orphan indication given limited patient populations (and likely assuming point 1 above).

Both points could apply to an orphan indication; an orphan indication has, by definition, a limited patient population, and many orphan indications are serious. A serious orphan indication falls into the “sweet spot” in which FDA may be willing to show flexibility and accept a single adequate and well-controlled trial.

After considering points 1 and 2 below, FDA must review the single adequate and well controlled trial to determine if it is sufficiently robust and compelling; i.e., does it feature any of 5 characteristics that could make it adequate to support an effectiveness claim (in other words, sufficiently robust & persuasive; FDA’s typical prior to reviewing the data is that the determination will be a review issue):

1.   A large multicenter study
2.   Consistency across study subsets (large trial)
3.   Multiple studies in a single study (e.g., properly designed factorial studies)
4.   Multiple endpoints involving different events (i.e., prospectively identified primary and  secondary endpoints representing different beneficial effects)
5.   Statistically very persuasive findings

For orphan indications, characteristics 1 and 2 are difficult to achieve due to the need for large trials. Characteristic 3 is situational; the example provided by FDA highlights a combination therapy tested as both the combination and as individual parts. Characteristic 4 is typically incorporated into the study designs Rho reviews. Often, this item can be interpreted by sponsors as the “everything but the kitchen sink” approach. In our experience, multiple well thought out, differentiated endpoints can help FDA assess approvability; however, FDA will stress that these endpoints should be independent of each other.

Additionally, FDA will often request that the endpoints be hierarchically ranked; this preserves the overall alpha for the study by preventing companies from fishing for an acceptable endpoint should the primary fail. If the program hits on multiple, well-thought out, agreed upon endpoints, improves significantly on current therapies, and the disease is serious, FDA may consider a single trial appropriate.

Clinical Trial written in search barCharacteristic 5 is likely the most realistic situation orphan drug sponsors can achieve, in spite of the small sample sizes typically observed in orphan trials. Assuming the orphan indication is for a serious indication (as defined above), FDA will at times negotiate with a sponsor those outcomes considered sufficient to support approval with a single clinical trial. Such a strategy should be discussed prospectively with FDA prior to initiating the pivotal trial; assuming FDA agrees with the design, FDA may be willing to consider allowing the filing to proceed if either 1) a highly statistically persuasive and clinically meaningful outcome is achieved or 2) at FDA’s discretion, dependent on FDA’s review of the efficacy data, the severity of the disease, and medical need. In practice, this approach has a high chance of failure, as most companies who work on orphan products move into their pivotal study with either 1) very small proof of concept Phase 1/2 trials that hint at efficacy but are not robust or 2) uncontrolled Phase 2 studies that show efficacy versus natural history data but fail to achieve statistically significant results when conducted as randomized, double-blind studies.

That aside, recently, FDA has taken an active approach for approving products based on a single trial with certain therapeutic paths, particularly anti-infectives. The Limited Population Antibacterial Drug (LPAD) pathway allows antibiotics to be approved and labeled for small populations with unmet needs. As of October 2019, two products have been approved using this pathway with single clinical studies:

•   Arikayce (amikacin liposome inhalation suspension), for the treatment of lung disease caused by a group of bacteria, Mycobacterium avium complex, in a limited population of patients with the disease who do not respond to conventional treatment, approved with a single trial on a surrogate endpoint (sputum conversion); and
•   Pretomanid Tablets in combination with bedaquiline and linezolid for the treatment of a specific type of highly treatment-resistant tuberculosis of the lungs, which was approved with a single trial that showed significant benefit relative to historical controls.

The success of these programs demonstrates FDA’s willingness to be flexible when the benefit can be properly assessed and truly outweighs the risk in a specific patient population. However, companies should be cautious when developing an orphan product. Prospectively planning to properly assess efficacy outcomes in reasonably sized, randomized, double-blind Phase 2 trials will help companies make appropriate go/no go decisions earlier in a product’s life cycle, ultimately helping companies spend less time and money on unapprovable products.

How much does a clinical trial cost? Understanding the 8 major factors driving CRO bids

Posted by Brook White on Tue, Aug 15, 2017 @ 09:32 AM

how much a clinical trial costsThis is a question we frequently get in some form from Sponsors in early phases of development that are trying to figure out what it will cost to hire a CRO to conduct their clinical trials and associated regulatory activities. While the high degree in variability between trials would make it difficult to provide a single answer, we can explain what factors can drive costs up or down.

If you already have well defined information about your clinical trial, use this RFP specifications tool to request a more accurate and detailed estimate from Rho or another CRO.

Clinical Trial Cost Drivers

While there are many variables that can impact a clinical trial budget, these are some of the most common ones:

  1. Therapeutic Area: What therapeutic area or indication is the focus of the program?  Some will be more expensive than others.  For example, oncology studies are frequently highly complex and, in general, will be more costly than say an ophthalmology study with the same number of sites and subjects.
  2. Study Duration: How long will a study last?  Short studies like a seasonal allergy study where enrollment happens quickly and the treatment period is relatively short would typically be a less expensive study than one that may require many months of treatment and follow-up.
  3. Number of Patients: How many patients are needed?  The more patients needed, the higher the costs will be.  Later phase studies where an accurate assessment of efficacy is needed tend to be more expensive than earlier phase studies where establishing safety is the primary objective.
  4. Number and Location of Sites: How many sites do you need and where will they be located?  The more sites you need, the higher the cost will be.  Geography is also important.  In general, costs will increase for every additional country you add.  Also keep in mind that conducting studies in some countries will be more expensive than in others.
  5. Number of Labs and Procedures: The number and complexity of labs and procedures will impact the costs.  This includes direct costs from the CRO to monitor and manage the data as well as increased pass through costs from sites and central labs.
  6. Patient Population: Are you studying healthy or sick patient populations?  What is the prevalence of the indication?  This will impact your costs both in terms of safety considerations and speed of enrollment.  How much competition is there?  If you are working with a small patient population and multiple competing studies, this will likely drive up costs for patient recruitment as well as potentially increasing the enrollment duration.
  7. Clinical Monitoring Plan: How frequently do you anticipate needing monitoring visits?  The total number of monitoring visits is a key cost driver and will be determined by the frequency of visits desired as well as the duration of enrollment and treatment.
  8. Safety Profile: What are the safety concerns with the treatment and patient population?  The number and seriousness of adverse effects (AEs/SAEs) will impact costs, as will the need for a data safety monitoring board (DSMB) and any interim analyses needed to support it.

Looking for an answer tailored to your clinical study? Please contact us for cost estimates tailored to your program.  We're also happy to set up an expert consultation if you need assistance figuring out how these cost drivers apply to your program.

Kara Roberts, Director Proposals and Contracts, contributed to this post.

5 Tips for Creating an RFP

5 Tips for Creating a Request for Proposal (RFP) for Clinical Trial Services

Posted by Brook White on Tue, Feb 14, 2017 @ 11:13 AM

RFPs tips that allow apples to apples comparisons of clinical trial servicesIf you’re looking for a contract research organization (CRO) to provide clinical trial services, chances are you’ll need to create a request for proposal (RFP). In the complicated world of outsourcing clinical trials, using RFPs to gather comparable bids from CROs can be incredibly challenging. The good news is, with a little planning and time, you can create RFPs that will reduce inconsistencies among bidders and ultimately help you identify the CRO that is truly the right partner for the job.

Here are five tips for creating RFPs that will help you compare “apples to apples” and help the CROs better understand your needs, values, and selection criteria for your clinical trial services:

  1. Provide background information on your compound and program.  Information about other clinical studies completed or in progress, outcomes from preclinical work, regulatory strategy and even funding and marketing plans can provide context that will help a CRO understand your needs and give you a proposal that best addresses all of your concerns.
  2. Provide a protocol or protocol synopsis.  Details about the study, such as number of clinical trial sites, number of subjects, and type and frequency of procedures and assessments are important cost drivers and providing them will help ensure a more accurate proposal.  Also, an experienced CRO should also be able to make valuable recommendations based on your protocol.
  3. Provide detailed RFP information to get consistent costs. Be specific. Some examples might include:
    • Project specifications – What are the important details of your program? (Use our RFP specifications tool)
    • Project timelines – By when do you expect certain milestones to be met?
    • Responsibilities (CRO, sponsor, other vendors) – For which segments of your program do you need a CRO to provide clinical trial services?
  4. Provide additional details. The more details you can provide the better.  It’s also OK to ask questions of prospective CROsask the CRO to make recommendations. You can tell a lot about a CRO by the recommendations they make and how they make them.  However, if you ask CROs to make recommendations be prepared for potential inconsistencies in the assumptions made and pricing offered between different CROs. The following are some additional details that might be helpful to bidders:
    • Provide site locations if you have already determined which sites you want to use.  If you aren’t sure, ask for recommendations based on your target enrollment and timelines.
    • If you’ve already determined which sites you’ll be using, it is helpful to know whether they will use a central lab or local lab and also will they use a local or central IRB. This can have an impact on timelines and costs.
    • Make note of any additional vendors you need such as specialty labs, Electronic Patient Reported Outcomes (ePRO), translations, meeting planners, or imaging services.
    • Will you be using paper or EDC? The vast majority of trials are now using EDC, but there may be some small studies or specific circumstances where paper still makes sense.
    • Do you want your data output in CDISC format? Based on the FDA’s guidance, new studies must be submitted in CDISC format, so it is strongly recommended.
    • If you are planning an interim analyses or will need support for a DSMB, make sure to include this information.
    • Will you use automated subject randomization (IVRS or IWRS)?
    • What are your plans for clinical supplies and distribution (IP management)?
    • Are you interested in risk-based monitoring strategies?  If so, include this information in your RFP. Incorporating remote monitoring or targeted SDV strategies could impact the budget.What are your plans for clinical supplies and distribution (IP management)?
    • Do you want the CRO to be responsible for the TMF?  If so, ask about whether they use an eTMF and if so which one.
    • If you know you want to use specific vendors (i.e. you know you want to use Medidata RAVE for EDC), be sure to include that information.
  5. Other items to request from CROs:
    • Project team CVs including the project manager, lead CRA, lead data manager, medical monitor, and lead statistician
    • Summary of team therapeutic experience and experience running similar trials
    • Relevant company information
Download: RFP Specifications Tool


How Stable Is Your CRO?  And Does It Matter?

Posted by Brook White on Wed, Feb 01, 2017 @ 11:15 AM

CRO stabilityClinical trials are a costly business.  In 2013 alone, the biopharmaceutical industry spent nearly $10 billion on clinical trials.  Operational failures in clinical trials can increase those costs and create delays in time to market. So when you pick a CRO, you want to ensure that at best they are mitigating operational risks, and at worse aren’t introducing new ones. Stability can play a significant role in this.

Corporate stability

When looking to outsource to a CRO, there are several aspects of corporate stability that should be assessed:

  • How long has the CRO been in business? The newer the company, the more likely that they don’t have the overall experience you may need. Additionally, they have a shorter history with their clients, so it will be difficult to assess past customer satisfaction.
  • Are they financially stable? A company that isn’t profitable, has a lot of outside debt, or is under strain from shareholders or investors may be making short-term business decisions that aren’t in the best interests of your study or program. Worse yet, they could go out of business in the middle of your clinical study or run into cash flow issues that impact the success of your clinical trial.
  • Have they recently been involved in M&A activity, have they gone public, or are there plans to do so? This type of activity typically comes with significant organizational impacts that can bleed over into day-to-day activities. From changing SOPs mid-study to project team turnover, it rarely has a positive impact in the short-term for existing clients.

Consider incorporating questions about these topics into a request for information (RFI) or as part of the request for proposal (RFP) process.  These are valid questions that CROs are used to addressing, so be wary of companies that are reluctant to do so.

Client Stability

client stabilityA good measure of how well you will be treated once the contract is signed is the satisfaction of existing and former clients.  You should look for a CRO that has long-standing relationships with many of their clients.  You’ll often see CROs that have slides listing the logos of their clients or with testimonial quotes from clients.  That’s all well and good, but you need to check for yourself.  Ask for references whose work is of similar scope and for similar services as those you are planning to outsource.  Contact references directly rather than relying on the CRO to act as an intermediary.

People Stability

happy project teamEmployee turnover rates across the CRO industry are incredibly high. In 2015, CRO turnover was 25% despite the fact that team stability is a key factor in meeting sponsor expectations and in doing high quality clinical research. Make sure you ask both about turnover and about the tenure of your assigned team. A team with multiple members that have recently joined the company should be a red flag. In addition to company turnover, find out what you can about project team stability. Keeping a team together over the course of a study means less re-training, fewer mistakes, and less re-work. There is a learning curve with each new sponsor and product. If you are considering outsourcing multiple trials particularly within the same program, ask if the same team members can be assigned to future studies.

Learn more about selecting a CRO by checking out the outsourcing tips on our blog.

Download: RFP Specifications Tool

Top Trends in Drug Development from This Year’s DIA Annual Meeting

Posted by Brook White on Tue, Jul 12, 2016 @ 02:41 PM

During the last week of June, the Drug Information Association held its 52nd Annual Meeting in Philadelphia.  As one of the largest conferences in our industry, DIA covers a wide range of topics over the entire spectrum of drug development, and it would be nearly impossible to provide a comprehensive accounting of the meeting.  However, I will try to share the most notable trends and themes from the meeting.

Big Data

big data in drug developmentBig data was possibly the hottest topic this year.  Not only did FDA Commissioner Dr. Robert Califf participate in a panel session on the topic, but when listing his top four priorities, one of them was greater use of existing data in EMR/EHR systems.  At DIA, people were really talking about big data from a handful of sources—electronic medical records data, data from wearables, data from social and digital media and genomics (and other -omics) data.  FDA is taking a lead role in the use of big data and real world evidence through initiatives like Sentinel, which enhances the FDA’s ability to proactively monitor the safety of medical products on the market, and precisionFDA, a community platform for next generation sequencing (NGS) assay evaluation and regulatory science exploration.  Big Data is an idea that has been talked about for some time, but based on this year’s meeting it is clear we’ve moved beyond idea to reality.  For anyone wondering how soon we might see full genomic sequencing of all patients in a clinical trial, you will be interested to learn that the cost is now on par with a chest x-ray, Genentech has sequenced 30K genomes to date, and AstraZeneca recently entered into a partnership with Human Longevity to sequence 500K genomes over the next 10 years.

Patient Centricity is Still Big

patient-centricityPatient centricity was the theme of last year’s meeting, and continued to play a central role in this year’s meeting.  But while last year was big on ideas and optimism, this year saw early adopters sharing lessons learned from programs already up and running.  Patients and patient advocacy groups made up a noticeable group of attendees and were outspoken during sessions.  Several companies including Bristol Myers Squibb (BMS) and GlaxoSmithKline (GSK) shared specific programs and tactics they’ve been using to move to a more patient focused research model.  Some examples include creating frameworks that allow greater number of employees to engage with patients and the public about the work they are doing and developing minimum standards for patient engagement that reflect geographic and cultural differences.  From a regulatory perspective, patient-centricity made Dr. Califf’s list of his top four priorities.

7 Tips to Use Social and Digital Media to Recruit and Engage with Clinical  Trial Patients

The Swinging Pendulum on Outsourcing

swinging pendulum on outsourcingFor many years now, it seemed the trend was always to more and more outsourcing with innovator companies keeping fewer and fewer activities in house.  Several of this year’s outsourcing sessions are hinting that the pendulum on that trend may be starting to swing back.  From internal frustrations with outsourcing groups, to dissatisfaction with vendors in terms of both quality and performance, to the failure of preferred provider relationships to deliver on expected savings and improvements, the talk from a number of pharmaceutical and biotech companies is that they are keeping more work in-house. That said, there certainly is not agreement among sponsors or vendors/suppliers on this issue.  Many pointed to issues at sponsor companies such as refusal to hear feedback from CROs on the feasibility of their budgets, timelines, or study designs as well and disagreement between outsourcing personnel and study team personnel about the providers being selected.

Drug Development as a Calling

DIA opened with keynote speaker Dr. Larry Brilliant, a physician and epidemiology who participated in the World Health Organization’s (WHO) successful small pox eradication program.  Dr. Brilliant talked through a number of health research and outreach efforts that have dramatically changed the world for the better, including the small pox and polio eradication programs, the development of electrolyte solutions to treat cholera and diarrhea, and more recently the efforts of the Carter Center to eradicate guinea worm.  He brought into sharp focus the idea that what each of us in the pharmaceutical industry does has the potential to change the world for the better.  The idea of drug development as a calling was furthered by Dr. Califf’s call to all of us to donate the information in our electronic health records for the betterment of research and medicine—a reminder that we should be willing to open ourselves up in the same way that we ask patients and research participants to do.  Finally, several of the patient-centricity speakers focused on the value of identifying employees who themselves were patients or care-takers of patients in their private lives in addition to being part of the research and development process.  These people are uniquely qualified to help us better understand the patients’ needs and experiences.

Greater Engagement by FDA

Finally, it was interesting to me to see the level of participation by the FDA in this year’s meeting. While they always send some presenters and a larger number come just to attend, this year did seem different. Dr. Califf presented in multiple sessions and was open and engaging during Q&A sessions. Additionally, numerous sessions included speakers and panelists from the FDA providing valuable insight into their point of view.

Did you attend DIA this year? If so, let me know what you thought.

Craftsmanship in Clinical Trial Study Design

Posted by Brook White on Wed, Jul 06, 2016 @ 02:55 PM

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.

Free Webinar: Protocol Design

5 Ways Rho Keeps Employee Turnover Low

Posted by Brook White on Wed, Jun 22, 2016 @ 11:40 AM

Employee turnover rates across the CRO industry are incredibly high.  In 2014, the overall CRO turnover rate was 19.5% and was even higher (25.4%) among CRAs.  At Rho, we recognize that team stability is a key factor in meeting our Sponsors’ expectations and in doing high quality clinical research.  In order to maintain team stability, we have to keep employee turnover low—significantly lower than industry average.  How do we do that?

Company Culture

As is frequently said by Rho co-Founder Ron Helms, the goal should be that we are all happy at work 19 days out of 20.  While everyone has an occasional bad day, we strive to make Rho a place where people are excited to come to work each day.  For starters, we have an intensive hiring and on-boarding process that ensures that people who come work here will be a good fit here.  Every prospective employee is interviewed by a senior leader whose job it is to protect the culture we’ve built.  It is amazing how much more enjoyable work is when your co-workers are smart, fun people who are good at what they do.

Rho game roomThe physical work environment is important too.  We constantly look for ways to improve the work environment.  Recently, we’ve added a game room with TVs, video games, and ping pong; the RhoHUB which is a central gathering place for co-workers to grab a cup of coffee or sit and eat lunch from one of the food trucks; and a meditation room.  All employees have the option of a standing desk, and we’ve experimented with some other alternative arrangements like treadmill desks and stationary bike desks.

We also encourage employees to connect with the community at large.  Last year, in addition to a significant corporate gift to DonorsChoose.org, each employee received a gift card to donate to a classroom or school project of their choosing.  Each year, we have a BBQ and raffle fundraiser to support the March of Dimes and numerous employees participate in the March of Dimes Walk for Babies.

Finally, no discussion of Rho’s corporate culture would be complete without mentioning our core purpose and core values.  Our core purpose is to improve health, extend life, and enhance quality of life via corporate and research excellence.  Our core values are integrity, stability, innovation, quality, to think critically & creatively, profitability, agility & adaptability, a team culture, and great people.  These aren’t just words on paper—they regularly come up in meetings and are used in decision making.

Competitive Compensation and Benefits

This probably goes without saying, but offering competitive compensation and benefits is a crucial component of any employee retention plan.  We regularly review market data on salaries to ensure not only are we bringing people in at appropriate levels, but that throughout their tenure here employees’ compensation keeps pace with the market.  We also offer a generous benefits package that includes standard stuff like healthcare and retirement plans, but also some nice perks like a concierge service that runs personal errands for employees.

Opportunities for Growth and Advancement

project meetingRho has a comprehensive career path system that is designed to reward both the breadth and depth of skills that employees acquire during their time here.  We encourage all employees to explore areas outside their existing area of expertise because it makes them more valuable to Rho and more valuable to our clients.  We prefer to promote from within when possible, and the majority of our senior leaders came into their current positions this way.  Entry level employees are exposed to a broad set of functional areas and skill sets, and most spend at least a year or two in generalist roles before becoming more specialized in an area of interest.

Work-Life Balance

Rho fitness centerWe believe our employees are most effective at work when they have a fulfilling life outside of work.  In a world where many people never disconnect, we discourage checking email at night and on weekends unless truly necessary.  We want people to take real vacations where they don’t take work with them, call into meetings, or constantly respond to email.  We also realize that life requires flexibility, and we trust employees to make good decisions when setting their hours or deciding to work from home rather than come into the office.

Work That Matters

Last, but definitely not least, is the opportunity to do work that matters. The research we do solves real problems. From breakthroughs in preventing peanut allergy, to getting a new product to market that extends the lives of cancer patients, to life changing improvements for organ transplant recipients, Rho employees know that the work we do here matters.

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4 Reasons Low Employee Turnover Is Critical in CRO Selection

Posted by Brook White on Fri, Jun 03, 2016 @ 11:48 AM

Employee turnover rates across the CRO industry are incredibly high.  In 2014, the overall CRO turnover rate was 19.5% and was even higher (25.4%) among CRAs.  As a Sponsor selecting a CRO, why should this matter to you?  The higher a CRO’s employee turnover rate, the more likely that team members assigned to your study will change over the course of the project.  Project team stability can have a significant impact on the quality of execution, ability to meet timelines, the amount of time and energy you will need to put into oversight, and site relationships. While no CRO can guarantee zero turnover on your team, the ideal situation is that the team you meet during the selection process will be the same team present during study start-up and the same team at project close out.


quality.jpgClinical studies are complicated.  Over the course of a study, team members become entrenched in the details of the study—understanding the protocol, knowing the details in study plans like the data management plan and the clinical monitoring plan, and participating in investigator meetings and other study specific training.  As a result, things run smoothly.  Problems are less likely to be missed, risks are identified earlier, and fewer errors are made.  There is a human aspect as well.  CRAs that have a chance to develop relationships with their sites are more likely to catch on when something is amiss.  They know which sites may need a little more attention to keep up with enrollment projections.  Strong working relationships between functional area leads mean smoother hand-offs as well.  When the data manager and biostatistician have been working together from the outset, there are fewer surprises when it comes time for database lock.


time is moneyNew team members mean additional training, time spent reviewing study documents, and time getting up to speed on the study.  Even if it is a fixed price contract so there is no direct cost impact, the additional time spent on team member transitions may very well impact key milestones.  

Increase in oversight

oversightYour time is valuable.  As a Sponsor, you have a responsibility to provide oversight for your study.  With a stable team and proven track record, it is likely that over the course of the study you can back away from the level of oversight you are providing—how much time you spend reviewing status reports, how much detail you need in your reports, how frequently you meet with your CRO.  However, when key team members leave and new ones are added, the risk increases which means your scrutiny needs to increase.

Site relationships

handshakeSites that meet their enrollment projections and produce high quality data are crucial to the success of your clinical trial.  Consistent communication and strong relationships with their assigned CRA are needed to get the best performance out of your study’s sites.  If their CRA or other main contacts keep changing, it is hard to build and maintain those relationships.

Given that low turnover is so important, what can you do?  When it comes time to select a CRO for your next clinical study, make sure to ask about turnover rates, and specifically, about CRA turnover.  You should look for a CRO with an overall turnover rate around 10% and a CRA turnover rate of less than 15%.  Pay particular attention to the longevity of key team members.  Look for a team where most of the key team members have been with the company at least 3-5 years.  Finally, talk to prospective CROs about what they are doing to ensure team stability and how they will handle any turnover that happens during your project.

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4 Top Trends in Drug Development: DIA 2015 Recap

Posted by Brook White on Tue, Jun 23, 2015 @ 11:04 AM

Last week, the Drug Information Association held its 51st Annual Meeting.  As one of the largest conferences in our industry, DIA covers a wide range of topics over the entire spectrum of drug development, and it would be nearly impossible to provide a comprehensive accounting of the meeting.  However, I will try to share the most notable trends and themes from the meeting.


patient-centricClearly, one of the biggest take-aways from DIA was patient-centricity. While for many of us patients have long been the motivation for the work we do, patients now are playing a central role throughout the drug development process. In addition to their roles as patients in clinical trials and eventual consumers, patients increasingly are participating in all aspects of development, from study design to advisory committee meetings. As we make this transition, patient advocacy groups can be powerful allies in reaching out to patients.

Some keys to patient outreach and involvement are relevance, logistics, and psycho-social components. For patients to be on-board with trials, they need to understand why a study is relevant. Patients need to see the link between how their participation now can lead to improvements in treatment in the future. Often, patients are interested in the outcomes past their own participation. Keep them updated as trials complete and results are available.

Patients can also provide useful insights on logistics. What may seem like minor considerations to scientists and others involved in study design, could be significant when it comes to patient participation. Logistics around scheduling, childcare, and uncomfortable procedures can be a study’s downfall if patients aren’t willing to sign-up or eventually drop-out because of inconveniences.

There are psycho-social issues that should be considered for certain patient populations and conditions. For example, it is likely that diabetics would have little concern over using an injectable treatment. Many have already used injectable products or have at least considered the need to use them in the future. On the other hand, patients used to oral dosing may have objections.

Finally, one suggestion made by a patient advocacy group at the meeting was to have all members of the clinical study team spend a day with a patient from the population being study. Understanding their daily routines and struggles can provide important insights.

Social Media is Big—And Getting Bigger

social media and drug developmentNearly every track featured at least one presentation on social media. We are now moving past theoretical uses to real world applications in patient recruitment, medical information, safety monitoring, and even regulatory agencies.

Use of social media is becoming commonplace in patient recruitment. In addition to being a more cost effective option when compared to traditional media like broadcast, radio, and newspaper ads, it also allows for better targeting and reporting. For example, social media allows you to show ads only to those within appropriate demographic groups. Even demographic groups previously considered poor targets for social media, like the elderly or lower income populations, are increasingly online in one way or another. Additionally, Sponsors and CROs have largely found ways to address regulatory and privacy concerns.

Medical Information is another area where social media use is increasingly common. With several FDA guidance documents now in place, Medical Information professionals’ perspectives on social media are changing. Patients making contact with pharmaceutical companies are being seen less as a risk to respond to and more as an opportunity to engage proactively. While companies should still be careful to present scientifically-based balanced information, social media can provide an opportunity to correct faulty information and even respond to questions about off-label use in a non-promotional way.

Safety monitoring is another area primed for growth in social media use. With the question of how to deal with adverse event reporting through social media largely handled—be prepared for it and treat it the same way you would treat reports coming in through traditional channels—product safety professionals are turning their attention to ways they can use social media to improve patient safety. Dr. Ran Balicer of the Clalit Research Institute is pioneering a system to identify safety signals in social media and compare it to information being reported by clinicians and to regulators.

Regulatory agencies are embracing social media as well. FDASIA Section 1138 instructs the FDA to create a communication plan to better inform and educate consumers with a focus on communicating with underserved sub-groups. The working group at FDA is relying on social and digital media to build the core of this program.

Outsourcing Trends

Despite incredible growth in outsourcing over the past 20 years, Sponsors still struggle with the right balance of outsourcing models. Both Sponsors and CROs report dissatisfaction with outsourcing relationships. Strategic relationships aren’t delivering the promised cost and time savings. The number of companies entering into strategic alliances and functional service provider relationships has been steadily growing over the past few years, yet virtually all Sponsors admit that they are still making outsourcing decisions (full service, FSP, or niche providers) on a study by study basis.

key performance indicatorsOne major challenge identified by several speakers is the ability to select key performance indicators (KPIs) that both accurately measure the CROs performance and those for which CROs are prepared to provide the data necessary to produce the metric. Existing KPIs have largely been selected because they are easy to measure and report on regularly, but they are often a better measure of the study design and the Sponsor’s ability to manage the relationship than they are a measure of the CROs performance. However, ability to produce metrics and willingness to be transparent continue to be make-or-break for Sponsors when it comes to selecting preferred providers, entering into strategic alliances, and picking functional service providers.

eSource, eTMF, and Risk-Based Monitoring

Perennial favorites, there was no shortage of presentations on the topics of electronic trial master file (eTMF) solutions, eSource and electronic data capture (EDC), and risk-based monitoring. Although eTMF has been a hot topic for a number of years, adoption is still slow. Many companies are considering implementing an eTMF, but most are still using paper systems, network file systems, content management systems, or a combination. However, growing Sponsor expectations for remote access to TMF documents combined with improved audit readiness will continue to push CROs in this direction.

risk-based monitoringOn the other hand, risk-based monitoring has become a reality for many studies. Companies have been investing in tools and processes and regulators continue to show support. As a result, more studies are taking advantage of the benefits of risk-based monitoring.

Although it has seen widespread (and in some instances near complete) adoption, EDC has left many feeling it hasn’t lived up to expectations. It hasn’t reduced significantly the cost or time of trials. Because much of the information clinicians need to record during study visits isn’t recorded in the CRF, information is still being recorded in one place and then transcribed into EDC. eSource—a combination of ePRO tools, EHR/EMR integration with EDC, and other electronic sources—offers new hope to deliver on the original promise of EDC.

Were you there? If so, use the comments to let me know what you thought were the most important take-aways from DIA this year.

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