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Trends in Clinical Trial Participation of Approved Drugs by Sex and Race: 2015 to 2019

Posted by Yael Symes on Thu, Feb 27, 2020 @ 10:00 AM
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Yael SYael Symes, PhD, Integrated Product Development Associate, has over 10 years of experience in writing and editing scientific documents, including 9 publications in peer-reviewed journals. She has participated in the authoring and preparation of clinical protocols, modules of NDAs and INDs, clinical study reports, and other regulatory documents in a variety of therapeutic areas. Dr. Symes received her PhD in Health Behavior at the University of North Carolina at Chapel Hill Gillings School of Global Public Health.    

In 2012, Congress directed the Food and Drug Administration (FDA) to investigate how well demographic subgroups are included in clinical trials in applications for medical products (FDASIA 907). The FDA responded by creating the Drug Trials Snapshots annual summary report to make demographic subgroup data more available and transparent. Drug Trials Snapshots summary reports include demographic data from pivotal clinical trials used to approve novel drugs (i.e., new molecular entities and original biologic products) each year by sex and race/ethnicity subgroups. 

Table 1 presents demographics by sex and race/ethnicity from 2015 to 2019.

Table 1: Demographic Summaries of Novel Drug Approvals from 2015 to 2019Table for Yaels blog

Trends by Sex
In 2015, 40% of clinical trial participants for the novel drugs approved that year were women compared with 72% in 2019. This increase may be due to drug developers’ efforts to recruit more women in clinical trials, but it also reflects the drugs that were approved specifically for women, including Vyleesi for treatment of hypoactive sexual desire disorder and Zulresso for treatment of postpartum depression. In 2019, 6 novel drugs were approved specifically for women compared with 2 drugs approved for men or boys.

Trends by Race/Ethnicity
In 2015, 79% of clinical trial participants for novel drugs approved that year were White, 5% were Black or African American, and 12% were Asian. FDA did not report Hispanic subgroups until 2017. In 2019, 72% of clinical trial participants for novel drugs approved that year were White, 9% were Black or African American, 9% were Asian, and 18% were Hispanic, which generally mirrored the 2019 demographics of the U.S. population (77% White, 13% Black or African American, 6% Asian, and 18% Hispanic; U.S. Census Bureau, 2019).

However, racial and ethnic minority participation varied widely by therapeutic area. In approvals for novel oncology drugs in 2019, 4% of study participants were Black or African American, 5% were Hispanic, and 18% were Asian. African Americans are more likely to be diagnosed with certain cancers and are more likely to die from some cancers compared with White Americans (American Cancer Society, 2019). It is important for clinical trial populations to reflect the racial and ethnic demographics of the intended treatment population.

Conclusions
Women and racial and ethnic minority populations have historically been excluded from clinical trials (Goldstein & Walensky, 2019; Liu & Mager, 2016). In 1977, the FDA discouraged including women in clinical research except for drugs tested to treat life-threatening conditions because they were considered a vulnerable population. The FDA reversed this stance in 1993 (FDA, 1993) and in 2019, the FDA released a draft guidance on enhancing the diversity of clinical trial populations (FDA, 2019). In the 2019 draft guidance, the FDA urged product developers to adopt practices that will allow clinical trial populations to reflect the diversity of patients who will use the product if it is approved.

Diversity in clinical research is important for ethical and scientific reasons. When women and non-White populations are not represented in clinical research, this limits our understanding of the safety and efficacy of drugs to treat important health issues in these populations. It is encouraging that women have become better represented in clinical research over time; however, there is still room for improvement to increase racial and ethnic diversity in clinical research, particularly in oncology. There are tangible steps that product developers can take to improve diversity in clinical research, including actions to reduce subject burden and foster trust (Symes & Modell, 2019).

References:
American Cancer Society. Cancer Facts & Figures 2019.
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf

Atlanta: American Cancer Society; 2019.Goldstein RH & Walensky, RP. (2019). Where Were the Women? Gender Parity in Clinical Trials. New England Journal of Medicine, 381(26), 2491-2493.

Liu, KA & Mager, NAD. (2016). Women’s involvement in clinical trials: historical perspective and future implications. Pharmacy Practice. 14(1), 708.

Symes YS & Modell, J. (2020). What Drug Development Sponsors, Contract Research Organizations, and Investigators Can Do to Increase Diversity in Clinical Trials. Journal of Clinical Pharmacology. 60(3), 281-283.

U.S. Census Bureau. Quick Facts United States: Population Estimates, July 1 2018. https://www.census.gov/quickfacts/fact/table/US/PST045218

U.S. Food and Drug Administration (1993). Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs, 58:39406–39416. https://www.fda.gov/media/75648/download

U.S. Food & Drug Administration. 2015-2016 Drug Trials Snapshots.
https://www.fda.gov/media/103160/download

U.S. Food & Drug Administration. 2017 Drug Trials Snapshots Summary Report.
https://www.fda.gov/media/112373/download

U.S. Food & Drug Administration. 2018 Drug Trials Snapshots Summary Report.
https://www.fda.gov/media/120253/download

U.S. Food and Drug Administration (2019). Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Draft Guidance for Industry.
https://www.fda.gov/media/127712/download

U.S. Food & Drug Administration. 2019 Drug Trials Snapshots Summary Report.
https://www.fda.gov/media/135337/download

 

Four Considerations for Every Rare Disease Development Program: Summary of CBI’s Rare Disease Clinical Development and Access Summit

Posted by Meagan Spychala & Karl Whitney on Thu, Jan 23, 2020 @ 09:17 AM
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Rho representatives joined regulators, industry scientists, and numerous patient-advocacy groups at CBI’s Rare Disease Clinical Development and Access Summit in Washington this past December. Attendees were able to share best practices in product development for rare disease programs in formal presentations and through informal networking. The following are 4 considerations for your development program that were highlighted during the conference.

1)  Seek early engagement for patient and caregiver perspectives and with key  payers.
Sponsors need patient and caregiver perspectives in order to ensure clinical studies are properly designed to provide evidence speaking to issues that truly matter to patients and their caregivers. These interactions should start as early on in the process as possible, even as early as initial animal proof-of-concept stage. Patient advocates advised companies to be open, transparent, and humble in approaching their communities for these insights; patients and caregivers want their perspectives heard and know that increasingly they have great influence in shaping product development for their conditions. Because of this increasing influence, some patient groups are not waiting for outreach from product developers, and have conducted or are planning formal Patient-Focused Drug Development or FDA listening sessions so that the community can proactively shape FDA’s understanding of key concerns Young pretty girl giving the sick woman glass of waterand priorities for product development.

It's also important to engage with key payers such as Centers for Medicare and Medicaid Services (CMS) no later than End of Phase 2 so that the pivotal studies can provide data that will support reimbursement. Often this means exploring persistence of effect in a longer study than might be minimally required by FDA. And, on that note, don't forget the perspectives of payers outside the US, including via the Health Technology Assessment processes in EU member states.

2)  Regulatory authority investment in rare disease development programs means more opportunities for dialog between regulators and sponsors: prepare for and embrace the increased access.
It is useful to note that in all these discussions about the development program, sponsors should make the most of milestone meetings and other opportunities to gain consensus with FDA on your plans. In 2018, 58% of the approvals were for rare disease indications and FDA speakers shared freely about how important and exciting this time is for them, patients, and industry. Precisely because FDA and similar stakeholders are so invested in these programs, and because these programs often include novel or challenging development issues, an iterative process in arriving at agreements should be expected. This will particularly be the case for topics lacking clear precedent owing to the rare nature of the disease in question. Therefore, it is imperative to identify key development questions and discuss them transparently with FDA and in hopes of settling key program questions by End of Phase 2.

3)  Plan early for Chemistry Manufacturing Controls (CMC).
Once your lead is selected, it's critical to provide sufficient resources and advanced planning to the CMC development program. All too often, especially for a program benefiting from enhanced support and guidance from FDA via Breakthrough Therapy or Regenerative medical pills industry  factory and production indoorMedicine Advanced Therapy designations, sponsors find themselves with near-complete clinical programs backed by incomplete CMC packages. Proper planning and support is the only way to ensure nimble scale-up as development proceeds and as the team begins to prepare for marketing. In that light, as much as possible, avoid tweaks to the investigational product to avoid having an even higher hill to climb for the CMC program. By the same token, if the product needs a specialized delivery device, work to settle the design and performance features of this as early as possible to allow the team to focus on other things like running efficient trials. Finally, the same plan-ahead advice likely applies to the nonclinical program. Interested in knowing more about how to plan for your CMC development program? In the near future, another blog post will address this topic, so be on the look-out.                                                                    

4)  Strategize for how to streamline your clinical trials while still supporting your claims.
In rare disease, recruitment and retention for clinical trials can be increasingly difficult due to the small population size. Creating a streamlined program strategy that will support your potential label will assist in a more efficient product development program. If the disease course, genotype, and phenotype are poorly understood, a natural history study is an absolute must to gain valuable information about the disease and potential endpoints that would be of value to your proposed claims. Remember that the first-in-human study may end up being the pivotal study, so it has to be well designed and as flawlessly executed as possible to deliver the best possible data. Perhaps this is easier said than done, but it's a fundamental pillar of successful product development, particularly for rare diseases. Even if your first-in-human study does not become your pivotal, you should look into alternative study designs that can reduce your sample size and discuss with the agency the composition of the program to understand the expectations for that indication and claim.

Topical, targeted industry meetings like this are excellent opportunities to share ideas and best practices in a small setting with a wide range of highly experienced people, which is why Rho staff regularly attend and contribute to such meetings. No meeting can offer a comprehensive view of everything that can come up in your development program or risks and opportunities to consider, which is why having an expert partner can be invaluable to your program. Contact us at any point in your development program for a free expert consultation; you'll be pleased with our team's thoughtful and creative review.

Meagan3-1

Meagan Spychala, PhD, Assistant Vice President of Patient Engagement and Program Strategy at Rho, serves as Rho’s expert on patient-focused clinical research activities and incorporates the patient and caregiver voice and experience into the clinical development program.  She recognizes the uniqueness of each clinical trial, which is especially true within rare disease clinical research, and understands the importance of each patient in the development program.

karlKarl Whitney, PhD., Assistant Vice President of Product Development, leads multiple integrated drug development programs spanning the development spectrum by planning, managing, and overseeing concurrent manufacturing, nonclinical, clinical, and regulatory activities. Dr. Whitney has also contributed to preparation of many regulatory submissions,  clinical protocols and amendments, and numerous other documents. 

 

Is a Target Product Profile Worth the Effort?

Posted by David Shoemaker on Wed, Dec 18, 2019 @ 09:32 AM
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David2

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
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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.

North American Cystic Fibrosis Conference: Key Takeaways

Posted by Lisa Payne on Thu, Dec 05, 2019 @ 09:00 AM
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The 33rd Annual NACF conference continues to be an action packed 3 days bringing together scientists, clinicians, health care providers, and caregivers to discuss the latest advances in CF research, care, and drug development.  These are our top 3 takeaways from the meeting and how they will impact clinical research moving forward.

We’ve come a long way, baby.

In the plenary talk on the first day, Marie Egan, M.D., provided an important overview of how far CF research has come over the past 30 years in her talk, “Emerging Technologies for CFTR Restoration in All People with CF”. This talk highlighted innovative technologies, including RNA therapies, gene therapies, and gene editing technology that hold potential to finding a cure. Dr. Egan also discussed the challenges and opportunities presented by these novel therapies as they advance toward the clinical study phases of development. Some of these challenges are very similar to what other rare disease communities are facing as the research of gene therapies increases. For clinical research, recruitment and retention in these trials (that can have a follow-up time of at least 5 years) need to be broached carefully, so participants understand the potential benefits and risks that await.

Excitement around Trikafta approval.

A week and a half before the conference, FDA’s approval of Vertex’s Trikafta was announced. With this approval, 90% of the CF community have a treatment option, which is an outstanding achievement. There was excitement around the approval and what this means to those with CF. What we are hearing from sites is that this also means ongoing clinical research studies are likely to have some delayed enrollment as patients start taking Trikafta. The delay will typically be the result of getting on to a stable dose to meet inclusion criteria, in addition to reduced resources at the site, as more patients are requesting appointments to switch onto Trikafta.

Medical News on Multicolor Puzzle on White Background.In the second plenary, Jane Davies, MD, MBChB, MRCP outlined the progress and promise of highly effective CFTR modulator therapies and the potential impact that Trikafta could have on this population. Whilst celebrating the success of effective modulator therapy, Dr. Davies also discussed challenges that remain, including treatments for people with rare mutations, caring for a patient population that has grown and aged, and providing access to CFTR modulators in more regions of the world.

CFTR modulators are not expected to eliminate the need for additional chronic therapies and drugs. While there is potential that CFTR modulators offer an opportunity to restore function earlier in life and alleviate a lifetime of lung damage that patients fight into adulthood, patients and families have expressed that reducing the treatment burden is a high priority and even patients on effective modulator therapies are not commonly reducing their other treatments. So while daily care has become increasingly effective, it remains complex and burdensome. This highlights the need for additional treatments and a cure for those with CF.

We will not stop until CF stands for Cure Found.

Current NIH director Francis Collins and his team helped discover the cystic fibrosis gene and he emphasized that the recent approval of Trikafta means that 90% of the community have the potential to receive a remarkable treatment; however, there are still patients with CF who might not benefit from this new therapy (including individuals with rare and nonsense mutations) and we must not abandon the 10% of people for whom these drugs will not provide benefit. Work towards finding a cure for all is just getting started.

A new era in CF research is beginning. The CF Foundation recently unveiled the “Path to a Cure” initiative, which will focus on finding treatments for the underlying cause of CF and a cure for every person with CF. The CFF is challenging academia and industry to accelerate progress in CF drug discovery and development. To help this ambitious initiative, the foundation intends to allocate $500 million to the effort through 2025.

This new era means that other recruitment strategies and study designs should be considered to enroll and execute a successful trial. Understanding the new patient population will be critical, and will require being cognizant that the baseline disease severity will vary across the population. New clinical trials in the era of modulator therapy may also require new endpoints,Medicine doctor hand working with modern computer interface as medical concept-1 as incidence or severity of common endpoints such as pulmonary exacerbations may change. Innovative study designs should be considered, but will require an increased amount of regulatory interaction.

Despite this remarkable progress there are significant needs that remain. As the CFF president and CEO, Preston W. Campbell, III, M.D, stated “Don’t stop dreaming of a day when all people with CF can say, ‘I used to have CF’.” Prioritizing innovative approaches to find a cure is at the forefront of the CFF’s mind and a recurring theme at the conference was the sentiment that the most important and challenging work lies ahead – until CF stands for Cure Found.

Need support designing and executing your next CF trial? Ask our experts for help.

JamieA3Jamie Arnott, RN, BSN, OCN®, Rho Project Director, received her undergraduate degree in Nursing from the University of North Carolina at Chapel Hill.  She has extensive experience from both the CRO and sponsor perspectives in the oversight and management of clinical trial operations and outsourcing with more than 12 years’ experience in project management and over 20 years’ experience in healthcare as a practitioner and manager.  Prior to her tenure at Rho, Ms. Arnott was the Director of Clinical Trial Operations for a biotechnology company where she provided oversight and management for all clinical activity for up to four concurrent INDs.  Ms. Arnott has broad therapeutic experience with ENT indications, cystic fibrosis, and multiple oncology indications, including ovarian cancer, hematological malignancies, and advanced solid tumors; she has pediatric experience both within the oncology field as well as orphan diseases. 

Kristin Gabor-2-1Kristin Gabor, PhD, RAC, Research Scientist, has over a decade of experience in writing and editing scientific documents and publications across a variety of biological, clinical, and regulatory fields, which includes several publications in peer-reviewed scientific journals.  Dr. Gabor has led and participated in the authoring and preparation of clinical study reports, clinical protocols, annual safety reports, modules of regulatory submissions (NDA, IND, etc.), and other regulatory documents in a variety of therapeutic areas.  She has also coordinated document review for regulatory submissions and led the management of safety review committees for clinical studies.  She has experience in a broad range of therapeutic areas, including sickle cell disease, allergy, inflammation, and immunology, infectious diseases, rare diseases, atopic dermatitis, multiple sclerosis, and cystic fibrosis.  Dr. Gabor earned an interdisciplinary PhD in Functional Genomics from the University of Maine and subsequently received an Intramural Research Training award from the NIH/NIEHS for her postdoctoral studies investigating the role of cholesterol metabolism and cell membrane perturbations in regulating the innate immune response in a rare genetic disease.  Dr. Gabor received her Regulatory Affairs Certification from the Regulatory Affairs Professionals Society (RAPS) in 2018 and is a current member of RAPS and the North Carolina Regulatory Affairs Forum (NCRAF).

NancyWsmallNancy Woody, MA, PMP, Senior Project Manager, has over eight years of project management experience in a clinical research organization (CRO) supporting and leading Phase 1 through 4 global and regional trials. Prior to working at Rho, Ms. Woody worked primarily on late phase and real-world evidence research studies and the collection of patient outcomes in standard of care settings and existing data sources. She has provided leadership to cross-functional clinical research projects and teams, virtually and co-located, in a wide variety of indications including Rare Disease (cystic fibrosis), CNS (Alzheimer’s, Multiple Sclerosis, spine pain, women’s pain, etc.), endocrinology (Diabetes) and oncology (Multiple Myeloma). As the project manager, Ms. Woody’s responsibilities include the creation and maintenance of project management plans, advising on operational strategies and mitigation plans, close collaboration with sponsor contact, and management of vendors, study team resources, timelines and budgets. She has a background in intercultural training and conflict resolution, which has helped to inform her work in risk management and mitigation on complex trials and within diverse teams. Ms. Woody is a certified Project Management Professional and received her Master’s degree in Intercultural Relations from Lesley University and a B.A. in Communication Studies from the University of North Carolina at Chapel Hill.

Cellular Therapy Studies: 7 Common Challenges

Posted by Brook White on Tue, May 15, 2018 @ 09:34 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.

Kristen Much, Senior BiostatisticianKristen Mason, MS, is a Senior Biostatistician at Rho. She has over 4 years of experience providing statistical support for studies conducted under the Immune Tolerance Network (ITN) and Clinical Trials in Organ Transplantation (CTOT). She has a particular interest in data visualization, especially creating visualizations within SAS using the graph template language (GTL). 

Cellular therapy is a form of treatment where patients are injected with cellular material. cell therapyDifferent types of cells can be utilized such as stem cells (such as mesenchymal stem cells) and cells from the immune system (such as regulatory T cells (Tregs)) from either the patient or a donor. In many cases, these cells have been reprogrammed to carry out a new function that will aid in the treatment of a disease or condition. Cellular therapy has become increasingly-popular largely due to the fact that cells have the ability to carry out many complex functions that drugs cannot. When successful, cellular therapy can result in a more targeted and thus more effective treatment. More information on cellular therapy can be found here .

Rho is conducting several studies using cellular therapy to treat diseases such as systemic lupus erythematosus and pemphigus vulgaris and for various applications within organ transplantation.

Cellular therapy trials offer their own unique set of challenges. The following list presents some of these challenges encountered here at Rho.

  1. Cellular therapies require highly-specialized laboratories to manufacture the investigational product, especially if the cells are being manipulated. Centralized manufacturers are commonly utilized requiring logistical considerations if the trial has multiple study sites. These logistics may include proper packaging, temperature storage, shipping days, etc. which all must be considered when shipping the product.
  2. It is critical to plan for and establish clear communication between the manufacturing lab, the study site, and the study team when working under time constraints. One common consideration is to ensure extracted cells will not arrive at the manufacturer on a Saturday or Sunday when lab personnel may not be available to immediately process cells. 
  3. Protocols usually require a minimum number of cells be available for infusion into the subject. The protocol must detail what steps to take when not enough viable cellular product is produced. Some questions to consider include: 
    • Is it is possible to recollect cells for a second attempt? If so, does it work with the timing of the trial?
    • Are there leftover cells from the first attempt? 
  4. Potent drugs are sometimes paired with administration of the cellular product.  It is crucial to avoid administering these drugs unless a viable cellular product has been produced. Checks should be in place to ensure product is available before administering additional study drugs.
  5. Guidance exists limiting the amount of blood that can be collected over an 8-week period from a single subject. If the cellular product is manufactured from a blood donation, the amount of blood from any and all blood draws around the same time should be taken into consideration. If the blood donation occurs close to screening when blood is often drawn for various baseline labs pay close attention to the total amounts as exceeding the established limits can be easy. 
  6. The subject accrual for a study should be clearly outlined in the protocol. Is it X number of subjects that receive a minimum number of cells, X number of subjects that receive any cells, etc.
  7. Cellular product may not be administered until several months into the study. Subjects may be evaluated for eligibility several times while waiting for the infusion allowing multiple time points each subject may become ineligible. This along with the potential of insufficient cellular product can result in an unexpected length of time to administer cellular product to the target number of subjects. As such, this is an important factor when determining the duration and budget for a cellular therapy study. 
All in all, there are numerous opportunities for learning when using cellular therapies to treat disease. In many disease areas, this concept is still novel and study teams are facing new challenges with each study. Understanding these challenges early can help in the development of a robust protocol that addresses these same challenges before they ever become an issue.

Breaking Bad (Meetings)

Posted by Brook White on Tue, Sep 19, 2017 @ 10:57 AM
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Ryan2.jpgRyan Bailey, MA is a Senior Clinical Researcher at Rho.  He has over 10 years of experience conducting multicenter asthma research studies, including theInner City Asthma Consortium (ICAC) and the Community Healthcare for Asthma Management and Prevention of Symptoms (CHAMPS) project. 

In Hamlet, Shakespeare posed the most famous existential question in English theater -- “To be, or not to be?”

If the Bard were to write a play for the 21st century office, he might ask a different, but no less poignant, question – “To meet, or not to meet?”

Few topics seem to elicit more workplace dread than the meeting. We tend to view meetings as disruptions, time sinks, resource devourers, and productivity killers. When someone says they “spent all day in meetings,” we don’t assume they got a lot accomplished; we assume their day was a bust.

Given the angst that seems to accompany meetings, we’ve been trying to rethink how we approach them at Rho. To help, we’ve been drawing inspiration from Deep Work, by Dr. Cal Newport. The premise of Deep Work is that our technology-driven culture is inadvertently inhibiting our ability to do focused, cognitively-demanding, high-impact work. Instead, our work is increasingly defined by fragmentation, interruption, and distraction, as we let our inbox and meeting schedule dictate the work we do.

Dr. Newport’s work struck a chord with us. Yet, we cannot escape the fact that our work requires the type of synchronous collaboration and context-rich communication that only meetings can provide. Here again we have an existential question: If meetings are so fundamentally important to our work, why are they so painful and disruptive?
Our honest take: We’re bad at them and we overuse them.

Most of us stink at meetings. We stink because we’ve fallen into the trap of thinking that meetings are easy. We show up and talk about the same stuff every week for an hour. What’s hard about that? In reality, effective meetings require thoughtful planning and careful execution from leaders, as well as mindful preparation and active participation from attendees.boring_meeting.jpg

Calendar software has exacerbated our problem by making it too convenient to schedule meetings. Rather than stopping to think if a meeting is needed, or if our objectives could be accomplished in a more effective way, we schedule the meeting because it’s easy. The classic example of this is the status update meeting. If the whole point of your meeting is to go around the room and give status updates to your teammates – something that could be done via email or chat with far less disruption – you have created a zombie meeting, an undead horror sucking the productivity out of your colleagues!

Many of us also have the bad habit of scheduling meetings as a form of procrastination. Instead of trying to solve a problem now, we punt it to our next meeting. While there’s nothing wrong with deferring a difficult issue until you can discuss it as a team, swamping the agenda with our postponed to-do lists is certain to “zombify” a meeting. The especially painful result of this tactic is that instead of taking a few minutes to solve the problem on our own, we multiply the resource burden. A 15-minute task dragged into an 8-person meeting effectively becomes a 2-hour task.

So, what’s to be done to salvage meetings and make them productive and engaging? One approach that we advocate among both meeting leaders and attendees is to follow the FSB mantra to meetings: Fewer. Shorter. Better. Here’s some advice we recently provided to our employees about FSB meetings:

Fewer – The challenge here is to not merely cut meetings, but to cut intelligently.  

  • Leaders: Think critically before you schedule a meeting.  Do you really need it?  Can you accomplish your objectives in a better way? For recurring meetings, take a look a day ahead of time and decide if you can cancel it. 
  • Attendees: Think critically before you attend a meeting. Do you need to be there? Read the agenda. Do you know which topics pertain to you? What will you contribute or learn? If you are unsure, contact the meeting coordinator and ask.
One alternative to cancelling a meeting is to rethink your meeting format. Could updates be sent from email and the meeting cancelled outright? Would a brief stand-up meeting suffice instead of an hour-long time drain? What about a brief teleconference from your desk? wood-table-meeting.jpg


Shorter – Meetings are notorious for taking up as much time as you allot for them. When you have back-to-back meetings, this leads to meeting room overlap, frustration, and the domino effect of late-starting meetings. Instead, try the 25/50 rule: reduce 30-minute meetings to 25 minutes and hour-long sessions to 50 minutes. This provides buffer to conclude your meeting and head to your next engagement on time.

Better – The single most important factor for better meetings is being prepared. Not knowing why you are at a meeting, what will be discussed, and what you hope to accomplish is certain to create a poor meeting.

  • Leaders: Serve your attendees well by following the basics of good meetings: 
    • Have a goal
    • Think critically about who should attend
    • Provide context ahead of time
    • Stay on time and on task
    • Endeavor to engage everyone in the room

If you are struggling with these steps, try setting aside time to prepare for your meetings.  You may also find that you are leading too many meetings.  In which case, you should share the load (this is a great way to help train up more junior team members!)

  • Attendees: Don’t settle for bad meetings.  Speak up and provide helpful, candid, and constructive feedback.  But also, when you’re in a meeting, be a helpful attendee:
    • Request that items be added to the agenda ahead of time
    • Come prepared to address the sections of the agenda you’re responsible for
    • Avoid the temptation to commandeer or disrupt the meeting

Meetings don’t have to be a source of frustration or disruption.  To the contrary, meetings can be some of the most productive times of our day – where we solve problems, brainstorm, and find creative inspiration – provided we execute them properly.  

When is the last time you did a self-evaluation of your meetings?  If it’s been a while (or never), consider taking 15 minutes this week to think critically and creatively about your current meetings.  How can they be pared back, truncated, and refined to make them more effective and productive?  When done right, following the FSB mantra can do a lot to return some much-needed productive time to your schedule.

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Beating the Odds: 5 Strategies to Improve Clinical Trial Enrollment

Posted by Brook White on Tue, Jul 18, 2017 @ 10:03 AM
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Brandy Lind, Senior Director OperationsBrandy Lind, Senior Director of Operations, has been in project management at Rho since 2004.  During this time, she has led several large programs and individual projects in multiple therapeutic areas.  She has worked on observational trials, interventional trials, and Phase I-III clinical trials throughout her career.

According to a 2013 report by the Tufts Center for Drug Development, timelines are typically extended to nearly double their original duration in order to meet enrollment goals which is a significant contributor to increased costs.  Hitting the clinical trial enrollment goal is not only important to meeting overall study timelines and budgets, it is critical to the success of the clinical study.  If you don't have enough participants, you won't have enough data to support your objectives.  That's why it's important to plan for enrollment just as you would plan for collecting and analyzing the data. In this post, we’ll share 5 keys to successful enrollment.

1. Identify sites with the most potential

choose the sites with the most potential, choose the biggest marbleIt all starts by choosing the right sites.  Research sites with experience in your therapeutic area.  Are there existing site networks that can be leveraged?  Check clinicaltrials.gov  to see which sites are currently participating in similar studies or have in the past. One of the best ways to find qualified, high performing sites is to reuse sites that have demonstrated both an ability to enroll and produce high quality data.  Past performance is one of the best indicators of how sites will perform on future studies.

Put the time in up front to complete a full feasibility.  It can be tempting to jump right into site start-up, but time and money spent on feasibility upfront can save you time and money downstream by preventing protocol amendments and enrollment struggles.  Ask sites about how they identify subjects, how many patients are already in their database, and how many patients come to their facility each month.  Find out what they do when they have exhausted their own database.  Competing studies can impact their ability to enroll on your study, so find out if they are currently conducting other studies in the same patient population.  If they are, press for information about whether they have access to enough patients for both studies or if inclusion/exclusion criteria are different enough to allow them to support both.

Get feedback from sites on the eligibility criteria and feasibility of operationalizing the protocol.  They may have suggestions for changes that can increase the enrollment rate without impacting the scientific integrity of the protocol.  The sites also know the patients well and can help you assess patient interest.  Consider whether the indication is serious enough that patients will want to participate and also consider existing therapies that are available to patients that may impact enrollment.

Study logistics can also impact patients’ willingness to participate, so consider the burden the schedule of events will place on participants.  How long will visits be?  Will they have to stay overnight?  Does transportation to and from the site present an obstacle for patients?  If you have an elderly or pediatric population, consider the impact on caretakers and how they will need to be involved in the process.  Sites can help you identify opportunities to ease these burdens for study participants and their caretakers.

Finally, prioritize sites based on start-up timeframe, recruitment potential, and previous research experience.  Make sure you also identify some back-up sites that can replace underperforming sites or be added later to boost enrollment.  You can achieve some efficiency by getting these sites through start-up along with the main sites you have identified.

2. Set expectations with sites

Make sure you set clear expectations with sites from the beginning rather than waiting until you start to see issues.  CRAs should work closely with each site to develop an individualized enrollment plan.  Where will they get patients?  What recruitment materials will work best for their site?  Are there other healthcare providers they can network with to gain additional participants?  A one-size-fits-all approach to recruitment rarely works.

Once sites are activated, have routine calls, individually and as a group, to discuss clinical trial enrollment strategies and plans.  Have sites share what’s working and what’s not, share ideas, and build relationships.  Find out from sites why patients don’t want to enroll.  If you do have to adjust the protocol, the earlier the better. During group calls, have your high performing sites share lessons learned, tips, and successes. 

Develop a plan for how you will address sites who are not meeting enrollment expectations.  Give them all the support you can, but also be prepared to follow through with your mitigation plan if they are not able to turn things around.

3. Start with accurate projections

start with accurate projections of enrollment ratesIt is tempting to create timelines based on best case scenarios.  Excitement about getting a new product to market, helping patients, and meeting investor expectations can all be strong motivators to be overly optimistic about enrollment projections, but this will just create more delays and increase costs downstream.  Be realistic about how many patients each site can enroll each month based on feasibility -- you (and your investors) don't want surprises!

Consider study-specific issues that may affect enrollment like seasonal effects.  Create graphics to show expected enrollment over time versus actual enrollment to date. Having this information at your fingertips can help you make informed decisions about whether to add a back-up site, change recruitment methods, and project when actual enrollment is likely to end.  Use this information to continually reassess your upfront assumptions, so you can be proactive if enrollment isn’t moving forward as expected.

4. Build relationships with sites

Maintaining strong relationships with sites is critical.  They provide key insights into the therapeutic landscape.  They are close to patients and can help you understand patient concerns and perspectives, which can help improve recruitment and retention.  

Use the investigator meeting as an opportunity to build and strengthen these relationships.  Explain the importance of the study and the potential benefits for the patient population.  Engage sites and make them a partner in your research. Creating a situation where sites want to work with you again will be of great benefit to future studies!

5. Collaborate with your CRO

handshake.jpgLook for a CRO that acts as an extension of your team and sees your study as a collaborative endeavor.  During enrollment, it's important to have constant communication between the Sponsor and CRO regarding the status of site activations and enrollment numbers, risks to the clinical trial if we are not on track to hit the goals, and mitigation strategies to get enrollment back on track.

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

Why Depression Studies So Often Fail:  Don’t Blame “Placebo Response”

Posted by Brook White on Thu, Jun 29, 2017 @ 02:34 PM
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Jack Modell, Vice President and Senior Medical OfficerJack Modell, Vice President and Senior Medical Officer, is a board-certified psychiatrist with over 35 years of experience in clinical research, including 20 years conducting trials, teaching, and providing patient care in academic medicine, and 15 additional years of experience in clinical drug development (proof of concept through market support), medical affairs, successful NDA filings, medical governance, drug safety, compliance, and management within the pharmaceutical and CRO industries. Jack has authored over 50 peer-reviewed publications across numerous medical specialties and has lead several successful development programs in the neurosciences. Jack is a key opinion leader in the neurosciences and is nationally known for leading the first successful development of preventative pharmacotherapy for the depressive episodes of seasonal affective disorder.

Prior to joining the pharmaceutical and contract research organization industries, I was in clinical practice for twenty years as a psychiatrist and medical researcher.  And something I noticed very early on among my patients with major mental illnesses, particularly those with severe depression and psychotic disorders, was that they did not generally get better – at least not for more than a day or two – by my simply being nice to them, treating them with ineffective medications (e.g., vitamins when no vitamin deficiency existed), seeing them weekly for office visits, or by providing other so-called supportive interventions that did not directly address the underlying illness.  To be clear, this is not to say that kindness and supportive therapy are not critical to the patient-physician relationship (“The secret of the care of the patient is in caring for the patient” [Frances Weld Peabody, 1927]), but rather that kindness and support alone rarely make a biologically based illness substantially improve or disappear. 

With this background, I vividly recall my surprise upon being asked shortly after I joined the pharmaceutical industry:  “Can you help us figure out how to decrease the nearly 50% placebo-response rate we see in antidepressant trials for major depressive disorder?”  “Fifty percent?” I replied, incredulously.  “There’s no way that 50% of patients in a true major depressive episode get better on placebos or just by seeing the doctor every couple of weeks!”  “Seriously?” was the reply, and they showed me voluminous data supporting their figure.

I spent the next few years trying to figure out this apparent paradox.  Not surprisingly, the answer turned out to be multifactorial.  After careful review of internal and external data, as well as published explanations for high “placebo response rates” in clinical depression trials (much of which also applies to clinical trials in general), the following three factors emerged as being of particular importance because they are easily mitigated by proper trial design, thorough research staff training, and meticulous oversight of study conduct.

(1)  Subjects being admitted into clinical trials often had depressive symptoms, but did not truly meet criteria for major depressive disorder.  Examples include subjects with personality disorders whose symptoms wax and wane considerably with external factors (e.g., family or job stress), subjects with depressive symptoms in response to a particular stressor (not of sufficient severity or duration to meet formal criteria for a major depressive episode and likely to abate with the passage of time), and subjects who – for various reasons – may feign or exaggerate symptoms for the purpose of seeking attention or gaining access to a clinical trial.  Unlike the patients I encountered in my clinical practice, subjects with these presentations often do improve with supportive interventions and placebo. 

Recruitment of truly depressed subjects is made even more difficult by the widespread availability of reasonably effective medication options. Patients in the throes of a major depressive disorder, who sometimes have difficulty even making it through the day, are rarely keen to commit to the additional efforts, uncertainties, and treatment delays involved with a clinical trial when an inexpensive prescription for an effective generic antidepressant can now be filled in a matter of minutes. Indeed, as more and more generally safe and effective medications have become approved and readily available for a variety of illnesses, the motivation for patients to join clinical trials in the hope of finding an effective treatment has correspondingly decreased.

(2) The second factor is somewhat difficult to discuss because it sometimes provokes an understandable defensive response in clinical investigators.  Consciously or unconsciously, many investigators and clinical raters inflate or deflate clinical ratings to enable the subject to gain entry into, or remain enrolled in, a clinical trial.  Most commonly, this is done by subtly – and sometimes not so subtly – coaching subjects on their answers, or when subject responses or findings seem to fall in between scale severity ratings, by rounding up or down to a rating that is more likely to qualify the subject for the trial. 

The effect of this practice is diagrammed in the following figures, specific examples of which can be seen in these references.1-3 In Figure 1, the white bell-shaped distribution is the expected distribution in severity rating scores of an unselected clinical population presenting for clinical trial participation, let’s say with a mean score at shown at X̄n. Not uncommonly, what we see in clinical trials in which a certain scale severity score is required for study entry (depicted by the vertical light blue line, with a score to the right of it required for entry) is not the expected right half of this bell-shaped distribution, but rather a distribution like that shown by the orange curve, which is essentially the right-half of the bell-shaped distribution with a large proportion of subjects whose ratings fell short of required severity for study entry (to the left of the blue line) “pushed” to the right, over the blue line, so that the subjects now qualify for study inclusion, with the mean of those thus selected shown at X̄s.

Figure 1

depression-fig-1.jpg

At the first follow-up visit, when raters (and subjects) now have little incentive to influence rating scores to meet a pre-specified criterion, the scores of the entire included population are free to relax towards their true values and assume the pre-selection and more normally distributed pattern.  Moreover, subjects and investigators, expecting that the onset of treatment should coincide with at least some clinical improvement, may bias rating scores during this period to reflect this expectation even though the signs and symptoms of the illness may have yet to show true change.  During this same time, any actual clinical improvement will also result in the rating score mean shifting leftward (white arrow, figure 2), but because the measured change – from the initial X̄s of the selected population to the new mean (X̄n1; orange arrow, figure 2) – is generally much greater than a true treatment effect during this period, any real changes are obscured and the ability to detect a true drug-placebo difference may be lost.  While this early “improvement” in rating scores for subjects in clinical trials may appear to be a “placebo effect” and is often confused with it, this apparent improvement is instead the result of artificially inflated scale scores regressing back to their original true distribution, in combination with whatever actual treatment and placebo effects may have occurred during this time.  Unfortunately, the introduction of non-qualified subjects to the study and rater bias will continue to hamper detection of actual drug-placebo differences throughout the course of the study.

Figure 2

depression-fig-2.jpg

(3) Finally, investigators and site staff often do not fully understand the true objective of the clinical trial:  it should never, for example, be “to show treatment efficacy” or to show that a product is “safe and well tolerated,” but rather, to test the null hypothesis of no treatment difference or to estimate likely treatment effect, as well as to faithfully and objectively record all adverse effects that may emerge during treatment.  Likewise, investigators and site staff often fail to understand the importance of complete objectivity and consistency in performing clinical ratings, the intention behind and importance of every inclusion and exclusion criterion (necessary for their proper interpretation and application), and the destructive effect on the outcome and scientific integrity of the trial that even well-intended efforts to include subjects who are not fully qualified can have.  

Each of these three factors can skew both drug and placebo trial populations and results, making it appear that subjects “improved” well beyond what would have resulted had there been strict adherence to protocol requirements and objective assessment of study entry and outcome measures.

What, then, can be done to prevent these problems from sabotaging the results of a clinical trial?  Foremost are thorough and meticulous investigator and rater education and training.  All too often, perfunctory explanations of the protocol and clinical assessment tools are provided at investigator meetings, and “rater training” takes the form of brief demonstrations of how the rating scales are used and scored, without actually testing raters to be certain that they fully understand how the scales are to be used and interpreted, including understanding scoring conventions, criteria, and necessary decision-making.4  Even seemingly sound training has marked limitations both immediately and as training effects deteriorate during conduct of the trial.4-7 

Training of the research staff must include not only a review of the protocol design and study requirements, but detailed explanations about why the trial is designed exactly as it is, the importance of strict adherence to study inclusion and exclusion criteria, and the necessity for complete honesty, objectivity, and consistency in conducting the clinical trial and in performing clinical assessments.  Detailed training on the disease under study is also important to ensure that all site staff have a complete understanding of the intended clinical population and disease being studied so that they can assess subjects accordingly.  And, as noted above, rater training must include not only education on the background, purpose, characteristics, and instructions for each scale or outcome measure used, but trainers, as well as investigators and raters, should be tested for adequate understanding and proficiency in use of each of these measures. 

Meticulous monitoring during the course of the study is also essential to ensure continued understanding of, and compliance with, protocol requirements, as well as accurate and complete documentation of study procedures and outcomes.  Study monitors and others involved with trial oversight should review data during the course of the trial for unexpected trends in both safety and efficacy data, and not simply for identification of missing data or isolated datum outliers.  Unexpected trends in safety data include adverse event reporting rates at particular sites that are much higher or lower than median reporting rates, and vital signs that are relatively invariant or favor certain values over time.  Unexpected trends in efficacy data include changes in closely related outcome measures that are incongruent – for example, objective and subjective ratings of a similar outcome differing considerably in magnitude or direction, that are much larger or smaller at particular sites than those observed at most sites, that occur in relatively fixed increments, and that show unusually similar patterns or values across subjects. 

Finally, and perhaps most importantly, is that no matter how well-informed or well-intentioned investigators and raters might be, humans simply cannot match computers in objectivity and consistency, including of the kind needed to make assessments based on subject responses to questions in clinical trials.  Unless being programmed to do so, a computer cannot, for example, coach a subject on how to respond, nor would it inflate or deflate ratings based on feelings, expectations, response interpretations, or desired outcomes.  A computer faithfully asks the same questions every time, following the same algorithm, and records responses exactly as provided by the subject.  Indeed, several studies have shown that computerized assessments of entry criteria and outcome measures in clinical trials – in particular interactive voice response systems (IVRS) and interactive web response systems (IWRS) – provide data of quality and signal-detection ability that meet and often exceed that obtained by human raters.1,3,7,8,9  For these reasons, strong consideration should also be given to using IVR and/or IWR systems for assessing study entry criteria and endpoints that allow such use.  

The author acknowledges John H. Greist, MD, for his outstanding research and input regarding these important findings and considerations.

References

  1. Greist JH, Mundt JC, Kobak K.  Factors contributing to failed trials of new agents:  can technology prevent some problems.  J Clin Psychiatry 2002;63[suppl 2]:8-13.
  2. Feltner DE, Kobak KA, Crockatt J, Haber H, Kavoussi R, Pande A, Greist JH.  Interactive Voice Response (IVR) for Patient Screening of Anxiety in a Clinical Drug Trial.  NIMH New Clinical Drug Evaluation Unit, 41st Annual Meeting, 2001, Phoenix, AZ.
  3. Mundt JC, Greist JH, Jefferson JW, Katzelnick DJ, DeBrota DJ, Chappell PB, Modell JG.  Is it easier to find what you are looking for if you think you know what it looks like?  J Clinical Psychopharmacol 2007;27:121-125.
  4. Kobak KA, Brown B, Sharp I, Levy-Mack H, Wells K, Okum F, Williams JBW.  Sources of unreliability in depression ratings.  J Clin Psychopharmacol 2009;29:82-85.
  5. Kobak KA, Lipsitz J, Billiams JBW, et. al.  Are the effects of rater training sustainable?  Results from a multicenter clinical trial.  J Clin Psychopharmacol 2007;27:534-535.
  6. Kobak KA, Kane JM, Thase ME, Nierenberg AA.  Why do clinical trials fail.  The problem of measurement error in clinical trials:  time to test new paradigms?  J Clin Psychopharmacol 2007;27:1-5.
  7. Greist J, Mundt J, Jefferson J, Katzelnick D.  Comments on “Why Do Clinical Trials Fail?”  The problem of measurement error in clinical trials:  time to test new paradigms?  J Clin Psychopharmacol 2007;27:535-536.
  8. Moore HK, Mundt JC, Modell JG, Rodrigues HE, DeBrota DJ, Jefferson JJ, Greist JH.  An Examination of 26,168 Hamilton Depression Rating Scale Scores Administered via Interactive Voice Response (IVR) Across 17 Randomized Clinical Trials.  J Clin Psychopharmacol 2006;26:321-324.
  9. http://www.healthtechsys.com/publications/ivrpubs2.html 

Webinar: Selecting Inclusion/Exclusion Criteria for Your Next Trial

Practical Strategies to Simplify Patient Centricity: Part 4—Practical and Easier than You Might Think

Posted by Brook White on Tue, Jun 20, 2017 @ 11:00 AM
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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 theInner City Asthma Consortium (ICAC) and the Community Healthcare for Asthma Management and Prevention of Symptoms (CHAMPS) project

This is the fourth in a series of blog posts on putting patient-centric principles into practice (view part 1,  part 2, or part 3)

In the previous post, we explored the rationale behind patient centricity and acknowledged the danger we face if we fail to pay heed to the rising tide of patient dissatisfaction with our trials.  In this post, we focus on the more positive and practical aspects of patient centricity, and how a patient-centered approach can improve our work and reduce our costs.

To start, I think it helps to step back and consider why we do what we do.  We are in the business of healing people, of eradicating painful, debilitating, life-taking diseases, and of giving people hope.  How do we do that?  

We rely entirely on the willing and voluntary participation of patients – the real heroes of clinical research.  When patients are in our trials, they put their body on the line, they give their time, they attend visits, they're poked and prodded, and they share blood and tissue and data with us so we can help heal others.  We have an ethical and moral imperative to do right by them.

superhero patient.jpgWhen it comes to ethical protections and patient safety and well-being, we have a number of invaluable guidances that steer our work – the Nuremberg Code, the Declaration of Helsinki, the Belmont Report, Good Clinical Practice, to name a few.  Unfortunately, our familiarity and history working with these seminal documents can sometimes lead to the misleading notion that we've "solved the patient rights stuff."  

However, we cannot be content to rest on our laurels.  We need to consider what lies ahead.  What is next on the continuum of evolving ethical milestones that define our work?  I believe patient centricity is a key aspect.  With patient centricity efforts, we are called to move past our historical approach of saying “we want to do this for patients" to saying “we want to do this with patients."  We change our traditional paradigm of “patient as a participant” to “patient as a partner” in the research space.  We invite patients to contribute their voice to what we're doing, to help us figure out what matters to them, and then we do it.

Of course, this leads to an inevitable question – how do we do that?  Answering the “how” question can seem daunting, especially given the apparent novelty of patient centricity as a movement.  A common impulse is to feel like this is “yet another” set of tasks to burden research teams.  Fortunately, “patient centricity” while relatively new as a term, is not new in concept. 

patient-centricity pyramid

Patient centricity is in our DNA as researchers. Yes, this is an "emerging trend,” but it didn't come out of nowhere.  It's a natural extension of a variety of disciplines and movements we care about – things like adherence, retention, patient advocacy, patient rights, patient-reported outcomes – all of which laid the groundwork for this.  Patient centricity isn’t so much a new trend, as it is a culmination of many different efforts that have been pushing us for years to better accommodate the needs and desires of the patients in our trials.

For example, we already know that patient engagement efforts lead to better recruitment and retention because research on these efforts shows the benefit of understanding and accommodating patient needs.  Likewise, research shows that engaged patients have better adherence and better health outcomes.

There are, rightfully, concerns about adding costs and time to our processes; but the good news is that the investments of patient centricity can prevent many of the “unforeseen” costs that commonly handicap our studies: delayed or insufficient recruitment, high dropout, and poor participant adherence.  What's even better is that research coming out of DIA and the Tufts Center for the Study of Drug Development (available to download here) shows that many of the simplest, most affordable, and lowest time-commitment investments promise some of the best returns.  They found that simple things like involving patient advocacy groups and patient advisory groups in study planning and development, and engaging patients on social media, can have some of the highest impact.

Consider also that patient centricity is a virtuous cycle.  Once you learn what works for a particular group of patients, you can build on that for future research and gain efficiency over time.  Likewise, as research sites and study teams develop reputations for good patient engagement, patients will be more likely to participate in future studies and advocate on your behalf to others in their social groups.

Patient centricity is still evolving as a movement, and you can expect to hear a lot on this topic in the years to come.  For now, the question is one of when to act.  Patient empowerment is happening in healthcare and patient dissatisfaction threatens our industry.  If you’ve experienced the pains of not being patient centric, through slow or stalled recruitment, poor retention, weak adherence, or disappointing patient-reported outcomes, taking a wait-and-see approach is a risky endeavor.  On the other hand, if you are motivated to adapt to the changing patient population, value continuous improvement, and want to see better return on investment, patient engagement is a good place to start.

To get you started, I propose a new acronym (because we don’t have enough in our industry as it is).

AIR – Ask, Inform, Respect

It’s pretty straightforward, but you would be surprised what keeping these principles in mind can do for your relationship with your patients.  To start, ask patients what matters to them and how we can better design trials to meet their needs, and listen to what they say.  Then, make an effort to keep patients as informed as you can throughout the project without threatening study integrity.  Ultimately, respect the patients.  Every one of us is going to be patient at some point in our life. We're only extending to them the same respect and empathy we would hope to get if we were sick, in pain, and anxiously hoping to find a cure that would improve our lives.

Webinar Registration: Putting Patient Centered Principles Into Practice