As the clinical trials industry sails into 2020 with the brisk winds of a strong R&D and innovative science pushing further into clinical development, the salary and satisfaction levels of clinical trial professionals are fairly strong as well. In late 2019, 

, along with our survey partner SCORR Marketing, surveyed our audience on compensation, current job satisfaction, and future career plans. This year’s Salary & Employee Satisfaction Survey shows that only half of respondents are looking for new jobs, and many who are leaving are doing so for better overall opportunities. SCORR Marketing’s own report based on the data is available for download 

	The majority of our respondents fell into the manager and director/executive director level of responsibility, each at 35%. For the years worked for an organization, the respondents were spread fairly equally from less than one year to five years, at 51%, and six years to more than 20 years, at 49%. And the size of the company based on number of employees was comparable-companies with ranges between one to 1,000 totaled 54%, while 1,001 to over 10,000 was 44%. Two percent were unsure.

	What all of this speaks to is the diversity of respondents, which represent the diversity of the 

	Jason Hersh, managing partner for executive search firm Klein Hersh International, told

 that the overall employment landscape in the life sciences is more robust and competitive than ever and shows no signs of slowing down. Hersh noted that this healthy hiring environment is driven by scientific breakthroughs in areas such as gene and cell therapy, biologics, and other fields of personalized medicine, which is empowering major innovation in drug discovery. This, in turn, has brought record levels of venture funding into the biopharma space, fueling the start-up of a multitude of new companies.

	“From an employment perspective, rapid biopharma market growth is driving an increased need for top talent to fill executive positions and manage critical R&D programs,” says Hersh. “With so many companies seeking to fill key management and scientific roles, the demand for talent is outpacing the available supply of top professionals with proven pedigrees.”

	Specific to the clinical trials piece, biopharma’s dynamic pipelines and significant cash resources has them in search of people to move their programs along. “This has made the hiring of clinical operations professionals to manage early- and late-stage programs one of the most competitive areas within the life sciences employment landscape,” notes Hersh. “There is an abundance of opportunities for clinical roles and all companies are essentially competing for the same talent.”

	Randstad US provides outsourcing, staffing, consulting, and workforce solutions within many industries, including life sciences, and it recently released its 

. John Ebeid, senior vice president of Randstad Life Sciences, told 

 that the 2019 projection for the demand for clinical trial managers held true, and continues into 2020. “If we look at the record number of FDA approvals in the last three years, along with the number of NDAs, and the amount of money that is going into R&D spend, we expect that to continue to drive demand for over the next five years,” he says.

	Another role in demand is drug safety specialists, which is seeing growth on both sides of the pharmacovigilance (PV) spectrum-in clinical trials and commercial. Ebeid notes that medical reviewers with an MD are needed to review cases, and RNs are needed to staff call centers for patients on already marketed drugs. Specifically, the report found that the PV market is expected to experience 10% growth, reaching $8 billion by 2024.

	Medical writers with technology, regulatory, or scientific experience are in significant demand. Finding such candidates with expertise in those areas is very challenging, says Ebeid. There were more than 30,000 job 

postings for technical writers-which includes medical writers-last year, according to the Randstad report, and the employment opportunities for this group is expected to grow 11% by 2026.

	While these roles are more recently in demand, Randstad did highlight the continuing demand to fill clinical research associate (CRA) positions, noting that there have been 4,000 job postings in the last 12 months alone. But the CRA role, historically, has also had challenges, which were noted in BDO USA’s recently released 2019/2020 

CRO Industry Global Compensation & Turnover Survey

. In that report, BDO found that CRA turnover rates in the U.S. reached a five-year high of nearly 30%. In addition, the report also stated that there has been little change in the CRO industry’s use of incentives in the U.S. since 2015.

	Judy Canavan, global employer services managing director at BDO, told 

that CROs are under intense pressure to contain their costs; however, the costs of high turnover to CROs are also significant. “There are the recruiting costs, and the loss of intellectual capital and the impact of their loss to the trial team,” says Canavan. “One of the questions on an RFP (request for proposal) will be, what is your turnover rate? Sponsors know that turnover will negatively impact their team, so it does benefit CROs to retain employees.”

	Clearly, the type of organization, type of position, and years with a company accounted for the salary ranges across the board, as seen in the chart at right.

	The majority of respondents do not receive either bonus or cash supplemental income, nor do they receive non-cash compensation. Half of the respondents received a 1%-to-4% salary increase in the past year, while 15% received increases between 5% to more than 20%, and 31% stayed at the same salary. When we evaluate how the survey respondents view their salary or compensation against other benefits, it becomes clear that cash isn’t always king. Ten percent of respondents listed inadequate compensation as a challenge, and 26% were considering a job change for better compensation. However, those factors trailed opportunities for career development, which was cited by 31% of respondents, and were closely aligned with professional advancement as the driver, at 24%.

	Hersh notes that it’s important for companies to provide professionals who have expressed a desire to learn and work with mentors those opportunities for career development-and the time to pursue them on top of 

their daily workload. “I think it goes to the bigger question of culture. We talk to our clients all the time about finding the right cultural fit during the recruitment process,” he says. “Equally important to finding leaders who have skills and expertise to help meet your scientific and business goals, is bringing on-board professionals who will embrace and advance your organization’s unique culture. Helping professionals to learn and develop new skills is a critical part of achieving that cultural buy-in once the candidate comes on board.”

	In the CRA role, Canavan points out that incentives outside of compensation are also important, but more difficult to achieve. Specifically, the CRA professional is harder to engage to create the glue or commitment to a particular company or organizational culture because they usually work from home and travel a lot. Canavan agrees as well that training or career development opportunities are critical and some CROs do offer that for CRAs, even though they know that the employee could take those skills to another CRO. “It’s a dilemma for them, but some do choose to make the commitment,” she says.

	The other issue is what Hersh mentions earlier-companies providing the time for employees to pursue that training or career development. “Some CRAs are so busy on projects, it’s hard to find the time to take advantage of these opportunities,” adds Canavan.

	Nevertheless, ultimately, the top answers from the 49% of respondents in our survey planning to leave their current position-better career development options, better training or continuing education, and professional advancement-all translate into more compensation. “All of these features would result in a

 higher compensation package,” says Canavan. She says that employees may be looking at their CV and see gaps-maybe they are limited by a specialty, say cardiovascular, and want to get more oncology experience. Or, again, for the CRA role in the robust employment environment (the unemployment rate reported in the U.S. was 3.6% as of October 2019), they can go to a pharma company, academic research center, or academia. “They have to weigh the pros and cons, maybe an academic research center has the same pay but has less travel,” notes Canavan.

	Hersh agrees that industry professionals are looking for new positions for a variety of reasons. “From a career development perspective, some candidates are attracted to opportunities to work in a new field of science, particularly in cell and gene therapy, or work as part of a broader clinical research team,” he says. “Professional advancement and compensation are also fueling a higher level of turnover among biopharma professionals currently. Some people are leaving positions with less than a year of tenure because they want to capitalize on the robust demand for clinical talent to gain a position at a higher organizational level, higher salary, or both.”

	In our survey, we asked, “Has another company ever recruited you (without you contacting them first) while you’ve been working at your current place of employment?” Seventy percent responded yes. Hersh explains the reasons for this finding: “We are seeing a marketplace for biopharma talent that is more competitive than 

ever. Simply put, supply and demand for talent is not even close to being aligned. There are many more opportunities available then there are qualified candidates to fill them. As I mentioned, companies are essentially competing for the same talent. Candidates, in some cases, are weighing multiple offers simultaneously. In this environment, relationships and the ability to tap into a broad network of professionals across the life sciences industry are critical to efficiently recruiting the right people to fill unique hiring goals and corporate priorities.”

	Ebeid also emphasized the competitive environment in the life sciences, and that candidates are receiving multiple job offers, especially in biotech hotbeds such as San Francisco, San Diego, and Boston. For those candidates, Ebeid says, “It really comes down to compensation and company culture.”

	While Ebeid doesn’t see any leveling off of interest in life sciences profession demands, he does foresee a change in skill sets and roles. “We continue to see record levels of R&D spend moving into areas related to aging, immunotherapy, and cell and gene therapy,” says Ebeid. “Also, there is continued innovation in many areas, including technology. So we will see roles that will couple scientific degrees with technology.”

	As big data, AI, and other data-related information technologies grow, Ebeid believes new roles such as computational biologist will become popular. “There will be completely new roles that didn’t exist before,” he says, alluding to his own degree in molecular biology. “When I graduated, you could go into research, or pursue a PhD into education. Now, with today’s technology and with that degree, we see demand for those with experience with assays, bioprocessing, and cell culturing-and that’s not just in life sciences. There’s a huge demand for that in healthcare and manufacturing.” 

http://www.appliedclinicaltrialsonline.com/salary-and-satisfaction

http://www.pharmexec.com/executive-search-tips

Articles

The perfect storm of industry growth, opportunity, and demand is translating to solid salary and satisfaction levels among clinical trial professionals, according to new survey.

Salary Survey: A Healthy Trajectory for Clinical Research Professionals

According to data from IQVIA Insights on the oncology pipeline (April 2019), of 15 new active substances launched in 2018, nine featured a predictive biomarker in their trial. Of those nine trials, one approved in non-small cell lung cancer could address over five million patients. The point is that it is a long-held belief, which appears to be bearing out, that as medicine trends toward more personalization, a biomarker of the disease will need to be a part of a patient’s work-up in order to be in a clinical trial and/or receive the approved therapy. In cancer, that could be in the tumor tissue identification, or a blood test, such as the PSA for prostate cancer. But also biomarkers exist for cholesterol and coronary artery disease and further into the genetic testing area.

	Many initiatives around using an individual’s lab tests, routine or otherwise, to find an appropriate clinical trial have been introduced in recent years. Somewhat of a holy grail is to match the right patient to the right trial via a biomarker. So when I recently read that 23andMe was 

, representing 14% of its total workforce, as well as cutting back on clinical studies, I was surprised. The reason for the move was a decline in consumer demand for the genetic tests, which is now leading the company to focus on building consumer trust in its genetic data, as well as focus on its work in therapeutics.

 include the launch of the Fox Insight Data Exploration Network, or Fox DEN. This initiative, announced in April of last year, joining The Michael J. Fox Foundation for Parkinson’s Research and the 23andMe network, contains patient-reported outcomes, de-identified genetic data, and data exploration tools from the largest cohort in Parkinson’s disease research, including, genetic information from 23andMe customers who have joined the Fox Insight study.

	There is also the recent announcement from TrialSpark and 23andMe, 

 that seeks to improve the clinical study recruitment space, using genetic data.

	Gaining or regaining the trust factor of a large consumer pool that has taken, or is now shying off from taking, a gene or ancestry test because of privacy concerns is a pretty big hurdle for a company dealing with the general public. And as our Managing Editor Michael Christel addressed 

 on patient health data, the ownership of such data is an area of concern. However, as also noted in the article, there is no such thing as an “average” patient, so how one person feels about sharing data and information, especially in a clinical trial, will not be consistent.

	Anecdotal information is that trial participants want to share data to improve their lives or the lives of others, but they also want that data shared back to them, as well as final clinical trial results. This will continue to be a space to watch.

From the Editor

Trial participants are willing to share data to improve their lives and the lives of others, but they also request that data and clinical trial results are shared back to them.


Gene Testing: Future Problem or Just a Blip?

The International Conference on Harmonization- Good Clinical Practice (ICH-GCP) is an international ethical and scientific quality standard that ensures the rights, safety, and well-being of clinical trial subjects are protected and that the clinical trial data generated are credible.

	Malaysia’s GCP guideline was developed by the National Pharmaceutical Regulatory Agency (NPRA) in 1999. This guideline adopts the basic principles outlined by ICH-GCP with some modifications to adapt to local conditions.2 The object of the Malaysia’s GCP guideline is to ensure that drug-related trials in the country are conducted in accordance with international ethical and scientific standards.

 Although there is currently no legislative requirement for GCP training, mechanisms were put in place to ensure that Investigators are trained on GCP. For example, it is mandatory to submit a copy of the principal investigator’s GCP certificate when obtaining regulatory approval from NPRA to conduct a clinical trial.

 In addition, all investigators must submit their GCP certificates for the ethics committee’s approval in Malaysia.

 Since the first edition of the Malaysian guidelines for GCP to the current fourth edition, approximately 12,000 clinicians have been GCP certified.

	It is recommended for GCP-certified personnel to be retrained on GCP guidelines every three years in order to stay current with updated regulations, standards, and guidelines.

 To that end, Clinical Research Malaysia (CRM), a research organization founded by the Malaysia Ministry of Health (MOH), has taken the initiative to conduct GCP refresher workshops for clinicians, nurses, allied health professionals, and study coordinators who have been certified with Malaysian GCP. The objective of the workshop was to provide a review on the principles of GCP, to improve participants’ skills and knowledge on managing the conduct of a clinical trial, and to share recommendations on how to conduct a GCP-compliant clinical study.

Since the first workshop on Oct. 4, 2016, CRM has conducted 31 GCP refresher workshops throughout Malaysia to about 450 participants at no cost. The majority of the participants are clinicians, nurses, and allied health professionals from government hospitals who are involved in clinical trials. Over the course of the conduct of the workshop, modifications have been made based on participants’ feedback to improve the quality and learning outcome of the workshop. A summary of the changes in the workshop agenda is listed in Table 1. As shown in the table, the pre- and post-workshop assessment test was introduced March 16, 2017, in order to evaluate the effectiveness of the workshop on participants’ knowledge regarding GCP. In this article, we analyze the pre- and post- workshop assessment score for workshops conducted since March 16, 2017.

	Before the start of the workshop, participants were required to complete 20 multiple-choice GCP-related questions (pre-workshop assessment). The questionnaires were then collected before the start of the workshop. When concluded, participants were then required to complete the same set of questions (post-workshop assessment). Participants were given 30 minutes to complete the questionnaire.

	The average score of the pre- and post- assessment results from participants of the same workshop was then calculated, which constitute one set of data points.

	The average score of pre- and post- workshop assessment from each workshop conducted since the introduction of the assessment on March 16, 2017, were compiled. Of the 28 workshops conducted since then, five workshops’ data could not be retrieved, hence, only 23 sets of data point were analyzed.

	The compiled average score of pre- and post- workshop assessment were then compared using Microsoft Excel’s T-test, assuming unequal variance to evaluate if there is any significant improvement in the average assessment score after the workshop.

Table 2 shows the compiled data from 23 workshops. Four hundred and twenty participants completed the pre-workshop assessment, and 434 participants completed the post-workshop assessment. On average, there is 20% improvement in the assessment score before and after the workshop.

	As shown in Table 3, the p-value is less than 0.05, suggesting that the improvement in the score is significant after participants attended the GCP refresher workshop.

	Training of investigators and allied health professions involved in clinical trials on the regulations and standards that govern clinical trials is important to improve the quality of studies and ensure maximum safety for study subjects. A survey among clinical researchers in Saudi Arabia on their ICH-GCP knowledge found that there is a poor understanding of investigators’ responsibilities on informed consent, and prompt reporting to the ethics committee.

 Hence, refreshing investigators’ awareness of their responsibilities could help to improve the performance of investigators in conducting clinical trials, particularly in these important ethical aspects.

	The GCP refresher workshop conducted by CRM fulfills its objective to provide revision of the principles of GCP to participants, with more than an average of 20% improvement in assessment score after the workshop.

	The factors that potentially contribute to the success of the CRM GCP refresher workshop in improving participant’s scores are explored ahead.

	Case studies were included for informed consent, adverse event reporting, and protocol deviations, for discussion.

	Participants were given real-life scenario case studies and they were required to answer guided questions in groups. The study has shown that case studies are more effective than textbook reading at promoting the learning of key concepts and comprehension of the relevance of concepts to real-life scenarios.

	Several methods were used to make the workshop interactive, such as games, quizzes, videos, group activities, and group discussion. Active engagement of participants helps to retain information.

	Trainers would also actively engage participants by asking questions and encouraging participants to share their experiences and practices. Regulations of clinical research can be understood more easily when participants can reflect the principles based upon their own experience.

	Participants were given an evaluation form at the end of the workshop to provide their feedback and opinion. Based on their feedback, modifications were made to improve the conduct of the workshop.

	The first GCP refresher workshop was a half-day (four-hour) workshop. Participants reflected that the workshop felt rushed and suggested to make it a full-day course. Subsequent workshops were then conducted one full day (eight hours) to ensure participants can learn at a better pace, contributing a better learning outcome.

	Based on early feedback, participants would like more activities, especially for safety reporting and protocol deviations. Modifications based on this feedback include the shift from a lecture-style workshop to an activity-based workshop. Presentation slides were also revised to be more concise to retain attention.

	Following feedback from participants, current edition Malaysian GCP guideline booklets were provided for participants to refer to during the workshop.

	It is important for investigators and allied health professionals who are involved in clinical studies to be trained on the latest GCP guidelines. GCP refresher workshops conducted by CRM were effective in refreshing participant knowledge on GCP guidelines. The success of the workshop could be attributed to providing case studies for discussion and interactive activities, as well as taking participant feedback into consideration. We would recommend other governing bodies to support the conduct of similar interactive workshops in their jurisdiction and to consider participant feedback for continuous improvement.

		Good Clinical Practice Network, n.d. ICH GCP Good Clinical Practice. Retrieved 05Nov2019 from: 

		National Pharmaceutical Regulatory Agency, 2018. Malaysian Guideline for Good Clinical Practice 4th Edition. Introduction to Malaysian Guidelines For GCP, Page 8.	

		National Pharmaceutical Regulatory Agency, 2017. Malaysian Guideline for Application of Clinical Trial Import Licence and Clinical Trial Exemption. Retrieved Nov. 5, 2019 from: 

http://www.nccr.gov.my/view_file.cfm?fileid=33

		Society Of Clinical Research Professionals Malaysia, 2016. A Guide to Conducting Clinical Trials in Malaysia, First Edition. Retrieved Nov. 5, 2019 from: 

http://www.clinicalresearch.my/wp-content/uploads/2017/03/A-Guide-to-Conduct-Clinical-Trials-in-Malaysia.pdf

		National Pharmaceutical Regulatory Agency, 2018. Malaysian Guideline for Good Clinical Practice 4th Edition. Forward to the Fourth Edition, Page 4.	

		National Institutes of Health, n.d. Good Clinical Practice Training. Retrieved 05Nov2019 from: 

https://grants.nih.gov/policy/clinical-trials/good-clinical-training.htm

		Al-Nomay NS, 2015. Compliance with ICH-GCP Guidelines among the Saudi Health Care Professionals: Should Saudi Arabia Conduct Widespread ICH-GCP Training? 

s. 2015; 1(2): 75-82. Retrieved Nov. 5, 2019 from: 

https://pdfs.semanticscholar.org/0112/2b2e7c0fdd762172251e807c273fcb4a399a.pdf?_ga=2.112527492.1640531090.1574928919-1845614418.1571207552

		Bonney KM, 2015. Case study teaching method improves student performance and perceptions of learning gains. 

. 2015;16(1):21–28. Retrieved Nov. 5, 2019 from: 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416499/

		Robin L. Bachelor Patrick M. Vaughan Connie M. Wall, 2012. Exploring the Effects of Active Learning on Retaining Essential Concepts in Secondary and Junior High Classrooms. Retrieved Nov. 5, 2019 from: 

https://files.eric.ed.gov/fulltext/ED531546.pdf

		Halkoaho A, Matveinen M, Leinonen V, Luoto K, Keränen T., 2013. Education of research ethics for clinical investigators with Moodle tool. BMC Med Ethics. 2013;14:53. Published 2Dec 12, 2013. Retrieved Nov. 5, 2019 from: 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867673/

 is Head of Clinical Operations, both from Clinical Research Malaysia

Feature Articles

Survey results from Clinical Research Malaysia’s GCP refresher workshop.

Is Retraining on Good Clinical Practice Guidelines Effective?

Despite the buzz, physicians have limited familiarity and understanding with the burgeoning category of nucleic acid-based therapies. New data sourced in September 2019 by InCrowd, a real-time market insights technology firm, provides a baseline on physicians’ current knowledge regarding the different types of therapies, their mechanisms of action, and their perceived current impact and future promise. Based on responses, the market shows significant knowledge gaps.

	Only 56% of screened respondents report being at least somewhat familiar with the seven leading nucleic acid-based therapies today-RNAi, siRNA, ASO, mRNA, AAV, CRISPR, and TALENs. Only 28% of physicians surveyed considered themselves familiar or very familiar with these therapies, and only 7% reported high familiarity.

	Oncologists have the highest familiarity of the specialists surveyed, at 52% (compared to 20% of PCPs and 15% of pediatricians). Physicians in academic settings noted greater familiarity (34%) than physicians in non-academic community practices (24%). 

	The terms mRNA and CRISPR are the most familiar, at 92% and 64%, respectively, for familiarity. Less than half of respondents were familiar with AAV (44%), siRNA (39%), RNAi (38%), and ASO (36%)-and less than a fifth (19%) with TALENS. Again, oncologists had the highest familiarity across terms compared to PCPs and pediatricians.

	Academic-based physicians reported higher levels of awareness on many terms. For example, 70% of academic practice-based respondents are familiar with CRISPR versus 58% in non-academic settings.

	There was a lack of knowledge around which among the list was a gene therapy. CRISPR, TALENS, and AAV are most commonly considered “gene therapies” by respondents, at 92%, 72%, and 67% respectively. About half associate the term with other therapies including RNAi (54%), siRNA (53%), ASO (51%), and mRNA (48%).

	CRISPR also led the ranking for promising treatments, at 27% among all respondents, and 44% among oncologists. mRNA ranked second, at 8% of respondents. Practice setting-academic vs. community-based-did not impact results.

	Understanding basic uses for nucleic acid-based therapies-like the use of CRISPR for permanent DNA edits, and the use of mRNA and AAV for the creation of vaccine vectors-varied between one-third to two-thirds of respondents. Significant confusion existed on:

		65% of respondents in academic practices, and 75% of oncologists, correctly identified that CRISPR Involves intentional and permanent changes at the DNA level.

		36% correctly said that CRISPR may cause unintended permanent changes at the DNA level, yet 35% said no other among the listed gene-based therapies did, when TALENS and AAV also risk potential unintended changes.

		Only 30% identified that AAV and mRNA can be used to make vaccines. 32% were unsure.

		A striking 83% of respondents are unaware of any approved nucleic acid-based therapies that are on the market-despite FDA approved Alynylam’s Onpattro and Novartis’ Zolgensma.

	The findings suggest biotechs and pharma firms face an opportunity for physician outreach and education on gene-based therapy fundamentals, as well as initiatives that build awareness of approved therapies and progress of others through the pipeline.

	The survey included a total of 250 clinicians, including PCPs (48%), oncologists (32%), and pediatricians (20%), with a near equal split between those academically associated (47%) and non-associated (53%) practices. Each respondent needed to have at least a limited familiarity with RNA- or DNA-based therapeutic methods at a minimum to complete the survey.

A Closing Thought

Survey data finds that physicians aren’t very familiar with the intricacies of nucleic acid-based therapies.

Back to Basics? Physician Awareness and Nucleic Acid-Based Therapies

FDA approved many new drugs and biologics last year based on limited clinical trials and utilizing accelerated review programs, notably to treat rare diseases and deadly cancers. In a report on Innovation in Drug Approvals of 2019, the Center for Drug Evaluation and Research (CDER) outlines these important gains, noting its use of expedited programs to advance access to 60% of 48 novel drugs 

	While last year’s numbers of new molecular entities (NMEs) falls below FDA’s record 59 approvals in 2018, the latest list includes numerous first-in-class therapies and advances in care across a range of conditions, from heart disease, macular degeneration, tuberculosis, osteoporosis, urinary tract infections, and migraine, to sickle cell disease, Parkinson’s disease, multiple sclerosis, and cancers and blood disorders. The report also cites numerous decisions to approve indications for expanded uses and additional patient populations, as well as new dosage forms for already marketed medicines, including the use of innovative adult therapies for children.

	These gains reflect CDER’s more efficient and predictable review process, as demonstrated by its success in meeting all user fee goals for timely assessments, reviewing 90% of applications in the first review cycle, and approving nearly 70% of new drugs in advance of other countries. The report points out that advances by sponsors in developing more targeted therapies for vulnerable patient populations, often based on genetic characteristics, benefit from the agency’s increased use of innovative and accelerated review procedures over the last four years.

	But while emphasizing gains in expedited drug development and review, CDER Director Janet Woodcock emphasizes that the agency’s “high standards for safety and efficacy have remained unchanged.” This responds to some fears that speedy approvals based on limited studies raise risks related to long-term safety and efficacy. Woodcock states that the agency is maintaining its high approval standards in utilizing innovative methods and new regulatory tools to 

expedite application reviews and approvals

 to bring “a wide range of new drugs to patients in need.”

	Support for innovative approaches to drug development also involves FDA public meetings and new guidances on a range of methods and policies for accelerating drug development and clinical studies. These include increased reliance on real-world data gleaned from electronic medical records, particularly for documenting additional indications of a medicine, for developing natural history studies, and to advance novel clinical trial designs for gene therapies.

Adaptive Design Clinical Trials for drugs and biologics

 issued in November sets out key principles for designing, conducting, and reporting results of such trials. In outlining recommendations for Bayesian adaptive studies, the advisory emphasizes the need to pre-specify rules governing such trials and appropriate ways to deal with deviations from the anticipated algorithm.

	The agency also supports flexibility in considering when and how only one clinical trial may provide sufficient evidence on a new drug, as presented in a December draft guidance on 

“Demonstrating Substantial Evidence of Effectiveness for Human Drugs and Biologics.”

 Debate has raged for more than 20 years over the traditional FDA requirement that all new drugs must be studied in at least two randomized, blinded, placebo-controlled clinical trials. And although randomized trials often are preferred for demonstrating the benefits of a new drug, “there are circumstances where evidence generated using a variety of clinical trial designs, endpoints, and statistical methodology can support effectiveness,” commented FDA principal Deputy Commissioner Amy Abernathy, 

. The guidance acknowledges that study designs with concurrent controls, active controls, and historical controls may be appropriate in certain situations-in addition to utilizing the “gold standard” randomized controlled trial (RCT).

	Meanwhile, FDA is taking steps to better monitor the safety and performance of both investigational and approved therapies. The agency has established a more efficient system for sponsors to report electronically adverse events involving study participants to 

 clarifies FDA’s new authority to require postmarketing studies and clinical trials for new drugs that demonstrate reduced effectiveness, in addition to those experiencing safety problems.

	Ideally, FDA flexibility in clinical trial design and more efficient application reviews will reduce the cost of clinical research and yield less expensive therapies for patients. So far, high launch prices for many critical new drugs benefitting from expedited FDA programs may cloud the larger benefits of these regulatory innovations and ultimately support legislation setting price controls for drugs.

News

Gains in FDA approval of new drugs and biologics last year are based on limited clinical trials and accelerated review programs.


FDA Cites Expedited Programs in Boosting Review Process

As cancer patients are surviving longer, there is growing interest in better understanding the potential for cardiovascular complications associated with cancer therapies. Indeed, over four decades, clinical data have shown that oncology treatments-from chemotherapies to targeted immunotherapies-can negatively impact heart health. Risks include ischemia, vascular disease, cardiomyopathy, myocarditis, hypertension, heart failure, arrhythmias, QT prolongation, and thrombosis.

 Often, patients face a tradeoff of the benefits and risks of treatment. Herceptin, for example, revolutionized the treatment of breast cancer, but also produced congestive heart failure in many patients.

	Thus, the FDA requires cardiac safety monitoring in oncology trials. And experienced clinical development teams understand and apply the evolving body of clinical research and therapeutic-level recommendations to clinical trial protocols in order to monitor for these cardiac conditions. Yet, the imaging required to monitor for cardiotoxicities during clinical development can, at times, be treated as a perfunctory task.

	The fact is, for cardiac safety trials, as in all clinical studies involving imaging, it matters how images are taken, how they are analyzed, and how the process is monitored. The quality and capabilities of the imaging management system-the process and tools used to collect, share, interpret, and store images-has an appreciable impact on patient safety as well as trial costs and timelines.

	Imaging is commonly used as a biomarker for safety in oncology development and, in many trials, is the primary efficacy endpoint. Echocardiography is used to assess symptomatic and asymptomatic cardiac dysfunction in oncology patients and to grade the severity of the condition; the results are surrogate markers for cardiac safety.

	The availability of high-resolution and sensitive imaging techniques allows for the identification of potential pathological changes earlier (e.g., decline in left ventricular ejection fraction (LVEF), acute myocarditis, and valve leaflet thickening).

	Such assessments are performed in order to:

		Make go/no-go decisions for continued drug development

		Assist in identifying high-risk subgroups within the population (for example, subjects with low ejection fraction or ventricular volume)

		Screen subjects for protocol eligibility

		Monitor patients for treatment-emergent changes, which may necessitate the need for dose adjustment or treatment discontinuation

	The study team will recommend the monitoring frequency based on an understanding of the drug’s mechanism of action, the intended patient population(s), the drug toxicity profile, and a review of prior clinical and non-clinical data.

	Early detection and diagnosis of cardiotoxicity is, of course, important, as the goal is to be able to medically intervene, prevent delayed effects, and improve outcomes for the patients. And, should the investigational product need to be re-engineered in the lab, it is better to determine this as early as possible in the development path.

	Increasingly, echocardiography is the primary assessment tool for cardiac safety assessments, given its advantages of wide availability, lower cost, and the improved detection three-dimensional methods afford.

	A critical factor in patient care and data integrity

	Several factors can impact the quality of data produced through echocardiography, as with other imaging modalities.

	First, the sonographer’s skill, experience, and knowledge can influence the quality of the image. Second, there can be variations in how the image is acquired, such as the display or resolution, which are related to the equipment itself. And, third, how individual readers interpret the images can-and does-vary. Studies conducted since 1947 have measured diagnostic discordance in the 25% to 40% range.

	Indeed, wide variability in both quantitative and qualitative echocardiography assessments is recognized in recent guidance publications offered by both the European Society of Cardiology (ESC) and the American Society of Echocardiography (ASE).

	Errors and inconsistencies can have a direct impact on patient care, as well as on the chance of regulatory approval for the investigational product. Thus, there’s a need for a comprehensive approach to ensuring that image acquisition techniques are standardized, that images are appropriately collected to the highest quality standard across multiple sites, and that the images are evaluated consistently to support the study protocol endpoints. That’s why imaging management systems and active reader management practices are critical. Additionally, the recent ASE Echocardiography Report recommends the use of a centralized echo-reading laboratory in multicenter clinical trials.

	Imaging management technology: Added transparency, reduced risk

	Today’s imaging technology platforms can help reduce the chance of human error, speed the assessment process, increase objectivity and consistency, and improve patient safety. A single system is used to collect the source data (which is input directly by the clinical trial site staff), manage image analysis, report on the results, and archive records. Because the data are always contained in the same system, there are no delays or errors caused by transferring it between different platforms to perform various operational tasks. This, in fact, eliminates virtually 100% of transcription errors. Furthermore, a consistent process is applied using standardized procedures in a common viewing platform.

 Imaging results are collected at the clinical site and are immediately available at the clinical institution, so safety signals can be identified at once for clinical decision-making. They are also immediately available to independent or blinded readers (BICR) so that they can make their independent assessments. The results can also be shared with other stakeholders such as sponsors, cardiac advisory boards, and data and safety monitoring committees.

Visibility to all study data in near real time.

 Trial managers and medical directors have total visibility to all study imaging data, throughout the imaging life cycle. They can:

		Measure the degree of discordance between site-based and blinded, central readers

		Track the number of cases requiring adjudication

		Monitor for selection bias in adjudicated cases

	Such insight into reader workloads and performance makes it possible to quickly address issues around reader drift, variability, and bias, thus minimizing their impact. If, for example, it becomes clear from the metrics that a reader’s approach has changed, retraining can be provided so that the reader’s performance is consistent with others in the reader pool.

 The system delivers reminders and gives users automatic prompts so that images pass through the agreed-upon workflow from reader to reader to adjudicator as efficiently as possible. The process is not dependent upon a project manager to keep it on track.

 Image analysis software can direct a reader through the analysis of each imaging time point and even pre-process and segment anatomical structures of interest in lockstep with the study’s imaging charter and image evaluation protocol (IEP). This minimizes protocol deviations and ensures that each reader’s unique bias does not creep into the analysis process by focusing the reader on targeted endpoints whose workflows are outline in the trial-specific IEP. Artificial intelligence (AI) can be used to augment human assessment. Using AI in this way can reduce read times by as much as 50% and the need for adjudication by 20%. It would, in the process, increase speed and reduce costs.

	Active reader management: Added efficiency and effectiveness

	An imaging core lab will be concerned with all of the controllable factors that impact data quality, from data collection to image review and data analysis. The best practices of an imaging core lab include:

		Ensuring that the imaging endpoints support the protocol

		Selecting a limited number of independent readers based on their training and experience

		Managing the image assessment-starting with training on the system and standardizing the imaging protocol and reading criteria

		Monitoring reader performance periodically during the study to lower variability and adjudication rates (readers are asked to re-read cases to identify performance drift)

		Reporting on imaging status and reader performance with recommendations for discussion and intervention if needed

	The lab’s ability to monitor reader performance and oversee imaging progress is dependent upon the capabilities of the imaging management software.

	Ensuring the validity of cardiac imaging data points in oncology clinical trials is difficult, and the challenge must be addressed early in study planning to both protect patients and the integrity of the trial itself. Sponsors should:

		Look to both positive and negative results in early trials to determine the potential predictive value of cardiac endpoints.

		Identify patients at risk for cardiotoxicity and determine how to balance survival benefits with reduced cardiac risk relative to a patient’s quality of life. (There is a higher tolerance for adverse events in oncologic treatments, and the benefit/risk balancing point is different than in other disease states.)

		Clearly define the protocol-required cardiac assessments and measurement parameters to be obtained during the echocardiogram. This will help the clinical team understand patients’ clinical course and inform decisions on treatment adjustments that may be needed to maintain or restore normal cardiac function. The protocol should include details on the number of imaging findings required, together with information based on statistical analysis to assist investigators in managing patients.

		Establish a baseline of cardiac performance prior to treatment, perform serial assessments during the trial, and conduct a follow-up assessment post-therapy. 

		Pay particular attention to the technologies and processes used to ensure accuracy in how images are taken and interpreted.

	Questions to ask your imaging partner in cardiac safety trials

		Which system is used to collect imaging endpoints?

		How quickly are the data available? How easy is the analysis?

		What is the expected rate of reader discordance?

		What is the optimal number of independent readers for the trial?

		What has the adjudication rate been on similar trials?

		What process is used to monitor the timeliness and accuracy of reads?

		What process/technology is in place for creating an audit trail and ensuring compliance?

		What systems and training are in place to ensure that sites know how to follow the imaging protocol?

	Ensuring that imaging in cardiac safety clinical trials is managed expertly and with the benefit of the latest technology and careful oversight has broad implications for patient safety as well as trial cost and timing. Overall error rates can be reduced by as much as 20%, read times can be reduced by up to 50%, and adjudication rates can be cut
	by 20%.

		Blaes, AH, Thavendiranathan, P, Moslehi J. Cardiac Toxicities in the Era of Precision Medicine: Underlying Risk Factors, Targeted Therapies, and Cardiac Biomarkers; 2018 

 (Print ISSN: 1548-8748 38; Electronic ISSN: 1548-8756) published by the American Society of Clinical Oncology, Inc. (“ASCO”), volume 38, p764-774	

		Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC)

How new technology can impact cardiac imaging in oncology clinical trials and have broader implications for patient safety.

The Benefits of Advanced Imaging Management Systems

 about low reporting of U.S. clinical trials attracted attention in Europe too-and not just because the researchers were from Oxford University. Non-reporting has acquired a new and high profile in Europe, partly because of the European Medicines Agency’s (EMA) attempts to tackle the problem, and partly because of energetic social media campaigning. Since early in 2019, health campaigners in Europe have been publishing and publicizing similar failings among European researchers.

article revealed that three years after U.S. obligations on publishing clinical trial results came into force, fewer than half of clinical trial results are reported promptly, and a third remain unreported. The findings also identified non-industry sponsors-universities, hospitals, and governments-as worse offenders than industry, with trials sponsored by the U.S. government least likely to post results on time.

	To improve public disclosure and limit selective publishing of results, the U.S. Food and Drug Administration Amendments Act of 2007 required sponsors of most U.S.-regulated clinical trials to register and report results on 

 within 12 months of primary completion, irrespective of whether the results are positive or negative. In January 2017, clearer reporting requirements were laid down, backed up with fines of up to $10,000 a day for non-compliance.

	But high rates of non-compliance persist, with more than 2,400 trials breaching the rules, and the study suggests that poor enforcement is to blame. The authors estimate that had the law been strictly enforced, over $4 billion in fines could have been collected up to the end of September 2019. But it says that progress has stalled, with the proportion of compliant trials stable since July 2018. One of the study’s authors, Nicholas DeVito, from the University of Oxford, said: “The fact that the U.S. Government cannot comply with its own laws is particularly concerning.”

	In Europe, a highly critical report emerged in February 2019 alleging that academics were largely failing to report their clinical trial results in line with EU rules. The posting of all summary results in the EMA’s register, EudraCT, became mandatory for trial sponsors as of 2014-and the requirements will be reinforced when the EU’s clinical trial regulation comes into effect.

Social media uses transparency to highlight alleged gaps in clinical trial transparency and offers a more powerful approach to health campaigners.



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