Issue:June 2014

CLINICAL TRIALS – Outsourcing Early-Stage Clinical Trials: How to Mitigate Costs & Risk

The most comprehensive survey of clinical success rates across the drug industry to date shows productivity may be even lower than previous estimates. According to a report from Nature Publishing Group, Hay and colleagues conducted a detailed analysis of phase transitions of 4,451 drugs with 7,372 independent clinical development paths from 2003 to 2011.1 On average, the likelihood of successful transition from Phase I to Phase II was 64% and the probability of success from Phase III to NDA/BLA was 60%. Only 32% of the drug successfully made the transition from Phase II to Phase III. On average, the likelihood of reaching FDA approval (LOA) from Phase I was about 10%.

The successful transition rate from Phase I to Phase II was 60% in the period of 1991–2000. Insufficient or lack of clinical efficacy is the principal cause of program termination during development.2,3 Thus, strategies for risk mitigation have to focus on Phase II as that is where most failures occur. Achieving proof of mechanism in Phase II is one of the most important attributes of success. Drugs that achieved proof of mechanism (an integrated understanding of the fundamental pharmacokinetic/pharmacodynamic principles of exposure at the site of action, target binding and expression of functional pharmacological activity) in Phase II have the highest likelihood to be transitioned to Phase III and LOA.4

Thus, the Contract Research Organizations (CROs) outsourcing services market has witnessed significant growth in the past decade. This growth has been attributed to the rising costs involved in conducting various phases of clinical trials ranging from drug discovery up to post-marketing approvals. Pharmaceutical companies opt to outsource clinical trial activities to vendors capable of providing bundled services such as regulatory services, clinical data management, medical writing, site management, pharmacovigilance, risk-based monitoring, biostatistics, and protocol development. As a large number of molecules fail during the drug discovery process, outsourcing helps mitigate financial risks.5

Drug Development & Delivery magazine recently asked some leading CROs to describe the benefits of outsourcing early-stage clinical trials, the best way to recruit and retain trial participants, and how they help offset costs and minimize risk. Change to Participating companies include Covance, PAREXEL International, Sofpromed Investigación Clinica, SLU, and Theorem Clinical Research.

Q: Please describe your company’s service offerings as they related to early-stage clinical trials.

Dr. Potthoff: Theorem Clinical Research is a midsized provider of comprehensive clinical research and development services. We consistently plan and execute successful medical device, combination, and complex trials across all major therapeutic areas and have offices spanning the Americas, Europe, and Asia. Our team includes renowned scientists and global regulatory affairs experts, and we also provide staffing partnership solutions (including full-service, augmentation and FSP models) and world-class clinical bioinformatics and analytics capabilities. Overall, when it comes to Phase I-III development, we can work to any capacity our clients’ needs.

Mr. Ledesma: Sofpromed is a technology-based CRO offering a range of services for early-stage clinical trials, including regulatory affairs, site activation, enrollment support, monitoring, data management, pharmacovigilance, pharmacodynamics and pharmacokinetics study logistics, statistical analysis, medical writing, and project management. We also provide a suite of electronic Case Report Form (e-CRF), patient database, medical imaging, and biological sample management web tools to increase the efficiency of key Phase I processes.

Dr. Pretorius: PAREXEL offers a full spectrum of services, ranging from first in human (FiH) through proof of concept (PoC). Within this segment, we provide our customers a variety of early-stage development services and niche capabilities through an integrated early phase network, which consists of five Clinical Pharmacology units located in hospitals across the United States, United Kingdom, Germany, and South Africa, as well as a large number of partner/alliance units around the globe. Our full-service, in-house service offerings include protocol design and consulting, global and local project management and regulatory support, monitoring, and clinical conduct. Our offers also include bioanalytical services, data management, biostatistics, clinical pharmacokinetic/pharmacodyamic (PK/PD) and pharmacometrics, and medical writing services.

Mr. DiMatteo: Covance focuses on two critical aspects of studies: Scientific integrity and human subject safety. Covance Early Clinical Services draws upon a comprehensive continuum of services to drive more go/no-go decisions than ever before based on our FIH/SAD/MAD experience and human AME capabilities. Our end-to-end early clinical focus can save time for some clients, as we can begin scientific discussions to transition from healthy volunteers to patients. As early clinical research continues to demand more complex studies, we have additional groups dedicated to client solutions in early-stage clinical trials, such as clinical pharmacology, early clinical development, clinical data analysis and reporting, and molecule development.

Q: Early-stage trials have shown a dramatic rise in per-patient costs as clinical teams look to collect more data earlier in the drug development process. What factors impact clinical trial costs the most and how can companies reduce that impact?

Dr. Potthoff: There is a growing demand for more data earlier, and equally so, there should be a higher demand for more powerful ways to collect and utilize that data earlier. Technologies that can help collect and aggregate data into something useful, both when it’s collected and down the road, can play a major role in reducing costs. Along that same line of thought, making it easier for people to digest and communicate early findings is essential, and that goes beyond the technology. Instituting and upholding clear chains of communication lead to more efficiencies in early development.

Dr. Pretorius: The key drivers of cost include (amongst other things) increased Phase I study complexity, higher regulatory hurdles, and increased competition for patients. Companies can mitigate or reduce these increasing costs by:

 – Strategically partnering with vendors, and benefiting from learning curve efficiencies and economies of scale that a Strategic Partnership (as opposed to tactical engagements) outsourcing offers.
 – Employing a disciplined and targeted approach to early-stage drug development that focuses only on information that is absolutely required. However, this approach may hinder innovation – something that is at the core of
exploratory development.
 – Leverage innovation and technology (e.g., modeling and simulation, biomarkers, genomic data, risk-based monitoring, etc.).

We have actually reduced our Phase I price per volunteer considerably over the past few years given the unfavorable macro-economic forces at play in our segment.

Dr. Lang: The traditional drug development paradigm that focused efforts on moving drug candidates through the various stages of development has changed. The current focus is on rapidly reaching a PoC with a go/no-go decision. The advantage is that it de-risks later-stage development and costly Phase III failures. Although the individual costs for early phase PoC trials may increase, this has the potential to allow for an overall decrease in the pharmaceutical development costs as more compounds can be evaluated earlier in the development sequence and decisions to progress or not progress these compounds can be made earlier. Good PoC trials require biomarkers, novel designs to determine efficacy, which can cost more, but can be prudent cost-saving investments. There are also the costs associated with risk-based monitoring (RBM). Monitoring costs are a main component of total clinical trial costs. While not every trial may realize cost savings with the implementation of RBM, the majority of RBM studies would see a reduction in monitoring costs. The reason for this is RBM’s movement away from 100% source data verification (SDV) to a more targeted SDV approach, focusing on study risks and mitigating them with proactive management.

Mr. Ledesma: Factors impacting early-stage trial costs are mainly related to infrastructure and in-house specialized staff of dedicated Phase I units, intensive monitoring, demanding recruitment coordination and data management derived from dose ranging and toxicity assessments, the implementation of pharmacological studies with multiple blood extractions, and the need of imaging-based efficacy evaluations in oncology trials. Per-patient costs are dramatically increased when delays take place, so time to completion becomes a crucial financial driver. Expenses are even higher in orphan drug development for rare diseases requiring the activation of several sites in multinational settings. Sponsors can reduce costs by outsourcing with full-service technological CROs to alleviate operational burden through global coverage, local support, and innovative software tools to accelerate workflows. Regional CRO personnel, familiar with local authorities, ensure rapid start-up and close monitoring at lower expense. e-CRFs with effective built-in checks speed up data collection, diminish monitoring efforts, and shorten time to analysis. Cloud platforms should also be in place to save costs through centralized biological sample and medical imaging management.

Q: What are some best practices to boost clinical trial recruitment and retention?

Dr. Potthoff: One is to strive to work with as local of an understanding as possible. Having a physical presence in the places you’re doing research helps you better understand regulatory and cultural climates, as well as what patient recruitment methodologies work. As far as retention, there’s a lot of value in thinking through retention strategies ahead of the game and how incentives will best appeal to the patients you’re targeting. The best recruitment and retention practices for trials are unique to the product at hand and the patients being targeted, and therefore, so should the approach to building the strategies to fulfill enrollment. You need dualistic intelligence — both of the product being developed and the patients you need to reach — and you need to have people who know how to build a plan that will bridge the two.

Mr. Ledesma: Educating investigators and potential participants is the first key to successful trial recruitment. Research teams must understand the factors influencing patient decisions. For example, although Phase I trials are usually focused on the safety and pharmacology of a drug, patients should know that these studies can be therapeutic, and not necessarily toxic. Good education related to trial-specific procedures and safety aspects encourages participation. Concerning retention, patients appreciate kind visit reminders, accessibility to site staff, avoiding lengthy and uncomfortable procedures, as well as receiving educational information and personal appreciation. Nevertheless, retention plans will also depend on the specifics of each trial, such as study design and regional aspects.

Ms. Weir-Hauptman: Successful clinical trial recruitment and retention are vital to preventing delays in completing clinical trials and moving forward with drug development. With today’s technology, more innovative means to recruit and retain subjects are being implemented to supplement the traditional means still in practice. For recruiting subjects, monetary incentives can attract healthy volunteer subjects. In early trials involving patients, while monetary reimbursement may not be possible, the ability to get free healthcare can be an incentive. Additionally, with both healthy volunteers and patients, providing transportation to and from the clinical site could also encourage participation. Meeting recruitment goals also comes from engagement from the clinical sites. Tools for these sites include advertising material (brochures, radio scripts, flyers) and funds for such advertising and for reviewing patient charts. Social media has proven to be an effective medium for advertising clinical trials and can greatly aid sites in recruiting patients. Also, conducting a recruitment meeting for all investigators during the trial can boost morale and motivate sites to put forth effort to recruit patients. For longer studies that require either long stays in-clinic or frequent visits to the clinic, patient retention is imperative. Tools that provide information about the clinical trial’s importance, procedures, and appointments can greatly aid in retaining study participants. A great tool for this is a mobile application that can house all this information in one location on the participant’s smart phone. The patient can learn about the clinical trial, receive appointment reminders, learn about the procedures that are being conducted at each visit, and learn about the investigated disease. The goal is to engage the study participant as much as possible to keep them committed to participating in the trial. For studies with a high withdrawal rate, it is important to determine why subjects are leaving the study and create educational material for both the sites and participants to prevent further drop outs.

Dr. Pretorius: In addition to traditional approaches (printed media, radio and television advertising community outreach, etc.), mobile devices and social media offer new and exciting recruitment channels. Digital enrollment in clinical trials is enhancing patient retention rates by creating an easy-to-use platform that not only aids in enrolling and tracking the patient, but also in providing disease-specific information and details about medication and office visits. Additional ways of reaching and retaining patients include online databases that contain information about clinical trials for various studies and open platforms that post trial details for patients interested in finding disease-specific information and enrolling for a trial. Despite the digital world in which we live, the most successful retention tool continues to be personal contact from site staff directly to volunteers/patients.

Q: Describe a customer project you tackled within the last year related to an early-stage clinical trial: the need of the client and how you handled the project.

Mr. Ledesma: We recently completed the management of a Phase I oncology trial consisting of the combination of an anthracycline antibiotic with a tyrosine kinase inhibitor administered to patients with liposarcoma of the retroperitoneum. The main goal of the study was to establish the recommended treatment dose of the combination for a future Phase II and perform a toxicity assessment based on dose escalations with cohorts of 3-6 patients. A total of 13 subjects were recruited, allowing the inclusion of a different sarcoma subtype without standard treatment available. The trial required the activation of 11 sites in Spain given the rareness of the disease. Our company provided regulatory authority approval, site activation, enrollment support, monitoring, data management, and pharmacovigilance services, along with the management of a pharmacodynamics study assessing expression levels of multi-drug resistance-associated proteins in lymphocytes. The trial required the review of baseline and post-treatment CT scans for each patient in order to evaluate tumor response. As added value, we provided our suite of web-based tools for data collection (e-CRF), blood sample, and radiological imaging management. A suitable combination dose was established after three escalation levels. The experimental treatment was not only safe, but showed encouraging evidence of tumor control.

Dr. Tong: One of our client companies was in early-phase testing of a novel therapy for cardiovascular disease. The regulatory environment was changing in this area in a way that could significantly impact the scope of the development program required. By sharing our experience in developing drugs in this therapy area, we were able to advise our client of elements to incorporate into its Phase II program to get preliminary data. We also used publically available trial data to advise them on timing of their program in light of other large-scale trials related to their drugs mechanism of action, scheduled to report out during their Phase II period. This allowed a staged investment in their drug project to put them in a position to go forward at full speed if these other trials enabled this opportunity, but limited their investment and resource utilization until that risk reduction milestone was achieved. It also allowed them to be in a position to know what to incorporate into their Phase III program based on regulatory guidance and outcome of other ongoing trials.

Dr. Pretorius: Let’s consider the early-stage clinical development of a compound to treat cognitive impairment associated with Parkinson’s disease and for Major Depressive disorder from first-into-human through to PoC. To reduce the standard projected early clinical development time (from 48 months to 24 months – i.e. 50% faster) as well as cost (making it 40% more cost effective), we could use several innovative strategies to accelerate global development. In order to facilitate the assessment of two therapeutic indications, we would use our functional domain strategy, where the mechanism of action of the molecule has common pathways of benefit, which can be evaluated by functional magnetic resonance imaging (fMRI) and Evoked Potential Biomarkers. When taking this approach, the sample size for these two small parallel PoCs is based on the anticipated neurochemical circuitry changes observed with this molecule and not powered based on the usual behavioral or motor outcomes used in Phase II. Hypothetically speaking, some of our innovations would include combining the first-into-human, single ascending dose and multiple ascending dose studies into a single combination protocol. Once proof of target engagement and/or CNS penetration was demonstrated in healthy volunteers, the study would include one healthy elderly patient arm to assess tolerability and PK, and additional Parkinson’s patient arms to determine the maximum tolerated dose in this target population. Guided by the above, including the identification of a potentially efficacious dose range, two PoCs should be conducted. One PoC study conducted in mild Parkinson’s patients with complaints of cognitive impairment, and the other in patients with Major Depressive Disorder who demonstrated clinically significant symptoms of anhedonia. To meet aggressive recruitment and enrollment timelines, we used a spoke and hub model, in which several outpatient investigators identified, enrolled, evaluated, and managed patients suitable for the study. All outpatient procedures were conducted at the investigator ‘spoke’ sites, which were geographically close to the hub, PAREXEL’s Early Phase Unit.

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 1. Hay et. al. Clinical Development success rates for investigational drugs. Nature Biotechnology, 32: 40 – 51, January 9, 2014.
2. Kola and Landis. Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery, 3: 711-715, 2004.
3. Sacks et. al. Scientific and regulatory reasons for delay and denial of FDA approval of initial applications for new drugs, 2000-2012. JAMA 311:378-384, 2014.
4. Morgan et. al. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discovery Today, May 2012.
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