Trials and Tribulations

Under pressure? John W, Hubbard, ICON Clinical Research, Diana L. Anderson, DL Anderson International, Inc., Lance Nickens, The Patient Recruiting Agency, and Elizabeth Moench, Medici Group, talk clinical trials.

NGP. What key factors determine the success of clinical development of a drug?
JH. There are many critical factors at each phase of development, from Phase I through Phase III, the transition from pre-clinical testing to Phase I being the first critical period. Essential is a thorough understanding of dose-scaling, from animals to man, in order that we are able to properly evaluate pharmacokinetic and pharmacodynamic properties, efficacy, safety and tolerability. Along with relevant information from pharmacodynamic testing using relevant biomarkers, this data will provide the basis for Phase II testing in patients.

The early period from Phase I to IIB establishes a sound scientific foundation, which enables the pharma or biotech sponsor to design the appropriate Phase III trials with appropriate inclusion and exclusion criteria to establish the safety and efficacy of the new drug in the target patient population. The challenge of many large Phase III multinational studies is identifying the centers around the world that can screen and enroll the thousands of patients necessary to complete Phase III testing.

Ultimately, to bring a product to market successfully and efficiently, the product sponsors need to understand all aspects of the drug, the patient population, healthcare policies in the relevant regions, and the competitive environment. Scientifically sound approaches – including effective trial planning, frequent discussions with regulatory authorities, objective analysis of existing and retrospective data, and clear assessment of the risk/benefit ratio – is critical to provide a sound foundation for effective drug development.

DA. The short answer is time, money, R&D and patients. There are many components involved in the clinical development process of a drug. It takes approximately 10 years of study in test tubes and laboratory mice to reach the point where the treatment might be tested for its safety and efficacy in humans. It could easily take as long as 15 years to bring a drug from its initial discovery phase all the way to market. Furthermore, it’s estimated that pharmaceutical and biotechnology companies spend over US$50 billion annually on research and development of new drugs, so it is a very expensive and time-consuming endeavor. Additionally, for a drug to ultimately be successful it must be tested in humans, therefore finding, recruiting and retaining patients plays an equally important role in this whole process.

Medici. Market forces have converged in the past decade to significantly increase competition for patients, while holding down costs due to delays. This mandates the need for patient recruitment efforts with clear milestones and deliverables. Patient recruitment programs today are, therefore, focused on timelines and cost containment.

Pricing pressures and the emergence of pricing control boards in more countries is also leading to profit regulation. In the US, prescription drug prices are the focus of Congress, the media and AARP – the largest organization representing the elderly. Pharmaceutical companies are being squeezed from both ends – pricing/profit pressures in the marketplace and regulatory pressures in R&D. The number of patients needed for an NDA, followed by post marketing surveillance and safety studies, essentially doubles clinical development costs. It’s wprth noting that the number of patients required per NDA have risen from approximately 1500 in the 70s to more than 5000 today. Patient recruitment and retention companies must deliver results, not promises to expedite study completion.

NGP. Just how important are clinical trials in bringing new drugs to market?
JH. Clinical trials provide the backbone for drug development. The cost of failure is one of main the reasons for the high cost of drug development, so the challenge is to reduce the number of failures and speed up development time. Clinical trial data provides critical information on the safety, efficacy and long-term effect of a drug. Effective clinical trials management, monitoring and reporting in all major therapeutic areas ensures patient safety, validity of scientific data and compliance with the many regulations that govern drug development. The quality and integrity of the data generated by clinical trials serves to minimize the risks and costs of product development and maximize the value of the product.

DA. Since no new medical therapy is allowed to be sold unless it is properly tested according to strict guidelines and procedures set forth by the FDA, it is impossible to have new drugs without clinical trials, so obviously it is extremely important. For every conceivable health condition, somebody is probably doing or getting ready to do a research study on it somewhere in the world. If we did not have clinical trials we would not have new drugs and devices that improve the quality of life for millions of people. The clinical trial process is the best, most effective methodology we have in place for testing new drugs and it is a critical component in bringing these drugs to market.

NGP. With this in mind, how much of a hindrance to clinical trials are problems of patient recruitment?
JH. Patient recruitment and retention is the largest cause of study delays in clinical trials – in fact, on average, most studies in the US are delayed by at least six months. According to reports, in 2001, over 85 percent of all completed medical studies experienced enrollment delays, and 34 percent were delayed for more than one month. Such postponements can cost pharmaceutical companies millions of dollars in sales. Today, this cost ranges between US$800k and US$5.4m per day of delay, depending on the potential blockbuster status of the product.

Difficulties in patient recruitment can also lead to site fatigue, frustration and loss of motivation, further impacting the momentum of studies. In this increasingly competitive environment, not having a recruitment plan in place could cause potential patients to move into rival studies.

DA. It all depends on the study that is being conducted. Every clinical trial has guidelines about who can and cannot participate. These guidelines are stipulated in the inclusion/exclusion criteria and are often based on age, gender, the type and stage of disease, previous treatment history and other medical conditions. Before a person can participate in a study they must qualify based on this criteria. While some studies want people who are healthy, others need those with a particular illness or condition, so it is clearly much easier to recruit patients for some clinical trials than others.

The cost to the sponsors of these clinical trials also varies, of course. However, by having a proactive strategy in place early in the planning processm refining their protocol, establishing a budget, determining the scope and depth of their patient recruitment needs, and carefully selecting the sites according to the target patient population they’re recruiting for, cost expectations can be reasonably managed.

LD. Clinical trials depend upon the public’s participation for completion of the studies. There are a decreasing number of potential patient populations in North America because of the growing number of clinical trials being conducted in any given area. In addition, recent negative media press and lawsuits have had a profound disruptive impact on the publics’ perception of the clinical trial industry and on their confidence in participating.

It is extremely important that we as an industry make significant efforts to reduce the impact that negative media has had. We must rejuvenate public opinion by offering them greater education and information about the clinical trial process, and the significant impact they have on our industry. This will serve to increase their confidence in making more educated decisions about participating rather than relying on negative media.

Medici. There is published data that suggests that on average 75 percent of clinical trials are delayed. While patient recruitment is often the most significant cause of delays, other factors also come into play, such as protocol amendments, IRB reviews and the number of productively enrolling sites. Therefore, when considering the costs of recruitment delays, many factors must also be included; such as the continued cost of monitoring, overhead costs for data management, the clinical team and site support.

NGP. What then are the problems pharma companies face with patient recruitment. Is it a case that they pay close attention to the scientific side of designing clinical trials, but fail to consider how they will get the patients to participate?
JH. Problems with patient recruitment can vary by study, so a strategic analysis of the protocol is needed from a recruitment perspective. This will identify demographic challenges, such as rare occurrence or hard to reach minority populations, or practical challenges, for instance the need for numerous visits or interventions, or competition to find a particular type of patient. Too often these considerations are made late in the planning cycle, sometimes even as a rescue situation. Patients today are more knowledgeable, challenging the medical professional with the demand to make their own choice.

Patient recruitment is a complex and intricate process requiring knowledge of human behavior, marketing and management expertise, together with the scientific expertise. Experience and research are required to analyze the protocol, to find optimal site locations, and to understand the demographics surrounding the media habits of the target subject population.

DA. Unfortunately, patient recruitment tends to gets overlooked until the last minute and the importance of it is often underrated. After all the hard work and the many years it takes pharma to develop a new drug – not to mention the cost - the patient recruitment component is sometimes taken for granted. A common misperception/misconception is that patient recruitment equals advertising and it is as simple as that. The reality is that while advertising is one viable option for stimulating enrollment, the nature of patient recruitment has evolved far beyond it being the only initiative. The key question related to all patient recruitment strategy is how to close the gap between marketing, advertising, technology and so on, resulting in study participation. I believe the answer is to develop a proactive recruitment plan encompassing a variety of resources that results in a successful comprehensive strategy.

LD. Patient recruitment is one of the most important obstacles that must be overcome in clinical trials. There is great pressure on the clinical trial industry these days, coming from four main sources, the first being pressure from the FDA to carry out more thorough testing. Secondly, the trend towards producing drugs for diseases and disorders that affect a smaller sector of the population is driving a need to reach smaller target populations for clinical trials. This problem is compounded by growing competition between trials looking for research patients in the same areas. Lastly, there is increasing negativity towards clinical trial research participation by the public due to recent negative media press.

Traditionally, the recruiting process starts with physician referrals. Today, however, relying solely on this method means most clinical trials will not meet their enrolment objectives, so other methods are needed to reach potential patients. The effectiveness and efficiencies of these techniques can vary, however, due to an overwhelming need to not only reach the greatest number of potential respondents, but also to elicit responses from a higher percentage of potentially qualified patients. Yet, at the same time, there is considerable pressure by sponsors on reducing recruitment budgets.

Medici. All too often, clinical teams are not prepared to deal with the business side of clinical trials, which includes assessing the cost of recruitment investment versus the cost of study delays. Biotech and venture funded companies, who live day to day with budgetary concerns, are more acutely aware of the financial impact of slow or lagging recruitment. Competition for patients requires enrolment services companies to specifically build recruitment forecasting models and incorporate real-time data on which decisions can be made on an ongoing basis. This takes recruitment to a new level – it becomes a science rather than a hit-or-miss approach.

Forecasts and cost models can clearly assess the risk of a ‘wait and see’ approach to launching a patient recruitment program, and at what point in the recruitment process a centrally coordinated and managed recruitment program should be implemented.

For patient recruitment and retention to be successful, therefore, planning and forecasting must begin from the start; working with clinical teams on site selection and recruitment preparation for study sites increases recruitment and retention success from day one. This is the ideal situation, since companies such as MediciGroup bring expertise to the table during the critical planning phases of a clinical trial.

NGP. How then can companies improve their recruitment processes?
JH. Companies need to ensure they include patient recruitment strategies in their early planning, including subject profiling, market segmentation, marketing communications planning, feasibility assessment, patient demographics, regional and country specific disease profiling, centralized pre-screening, and trial management.

ICON has expanded its patient recruitment capabilities through a new strategic partnership with global patient recruitment company Fast4wD Ogilvy. The relationship leverages the strength of both companies. ICON specializes in global site management at the point of care, while Fast4wD Ogilvy utilizes state of the art tools to enhance patient identification and marketing effectiveness. We can now offer leading edge solutions to clients in need of efficient patient recruitment and retention strategies in order to reduce costly delays of their studies and move their compound closer to regulatory review. It is more effective to build-in these strategies in the beginning of a study, rather than implement a rescue strategy when the study is already behind in enrollment.

DA. We’ve been in the patient recruitment business for over 13 years and have worked on studies in 25 countries. There are key elements that we’ve experienced on a consistent basis that have had a dramatic impact on the success of our patient recruitment efforts – planning, approach and communication. I can’t stress enough how important it is to have a solid, strategic plan in place early on in the process. Understanding your target patient population, knowing what sites you’ll be working with and where they are located are all very important factors. D Anderson & Company evolved from a clinical background, starting as a an SMO, so we have extensive clinical research experience and an in-depth understanding of what the sites need and how they operate.

The approach you take in trying to recruit patients is also very critical. There is no ‘cookie-cutter’ way of doing things where one size fits all. With every study we’re involved in, we take a unique strategic and creative approach depending on the therapeutic indication. Strong creative messaging, site education and support materials, customized training workshops, community outreach programs, patient and caregiver support and patient wellness kits are just a few things we consider for each study opportunity.

Communication is also a key factor in the success of a clinical trial. Having frequent conversations and updates between the sponsor, sites, IRB and patient recruitment provider lets everyone know what strategies are working and what things need to be adjusted in order to stay on track with recruitment goals.

LD. Beyond physician referrals, print is the most commonly used medium in patient recruitment. However, although it is easy to create and place print advertising, this also the most expensive method, yields the lowest efficiency, is the slowest in generating call responses, and is highly unpredictable. Radio is an effective medium used to target a particular demographic group, but can also be very expensive and potentially unpredictable. Online advertising is costly, highly unpredictable and a far less effective way to target a precise demographic.

There is a trend towards new approaches in finding patients using more efficient forms of advertising and web based or communication technologies, while finding efficient ways to reduce production costs. Using these techniques is proving to generate greater response rates.

The use of television advertising is traditionally perceived as too expensive to produce and too expensive to air. In fact, neither could be further from the truth. TV is less expensive than print and radio and is by far the most powerful advertising medium to use, delivering responses from more qualified patients, faster, and as a call-to-action medium, means you receive an immediate response once a spot airs.

Because TV is both an audio and a visual medium, the response exceeds that of print and radio, but it is vitally important that the TV commercial be appealing and motivates the potential respondent. With the growth over the past few years in the quality and the technology of equipment available to make these types of commercials, added to the increasing number of qualified and capable designers across the globe, it is now possible to create effective commercials at a cost point more palatable to the industry.

Medici. When companies work collaboratively with MediciGroup, the recruitment planning process begins with understanding the scope of the recruitment challenge and the intricacies of the patient population. Over the past 14 years that MediciGroup has been dedicated to recruiting and retaining patients for clinical trials, specific methodologies have been developed to help companies to improve their recruitment process. Several of these process have since been adopted in various forms and used by other recruitment companies. These include three steps: firstly, the Leaky Pipe Model – a model that uses historical and or actual data to project the number of patient contacts required from pre-screening to evaluable. The second step is Media Forecasting, which uses market data by media method, age demographics of the patient audience, and prevalence rate of the target medical condition. Projections are developed that forecast response by media method and, by coupling these forecasts with the Leaky Pipe model in Step 1, advertising response is calculated beyond randomized subject through to evaluable. Step 3 is Media Cost Effectiveness Analysis. By adding media costs, the effectiveness of each media method is assessed. Media recommendations are based on media methods projected to yield the greatest return on investment with the greatest number of patients expected to be randomized.

Feasibility and project need are based on assessment of the a number of factors. These include identifying where patients are in the healthcare system, and by whom they are being treated; the expected percentage of patients that meet study criteria; barriers to enrolment /retention and other factors that can potentially undermine study success; relative costs/benefits of media or recruitment method; and the location of sites relative to the patient population.

Each of these factors requires knowledge of the demographics and psychographics of study subjects, which MediciGroup takes into account for all studies. We successfully profiled the demographics and psychographics of families and girls with anorexia for a pivotal J&J study. As a result, recruitment was delivered on time – on the original target date even though the study was placed on hold for several months due to FDA hearings.