A Rising Tide for Clinical Services By Daniel Limbach June 2006 VIEW on Clinical Services Contract drug-development expenditures were $19 billion in 2005 and are expected to increase at an annual rate of 17%, eventually exceeding $42 billion by 2010. Clinical-service outsourcing is going through a major period of growth, and it will continue to increase at a healthy rate for years. A new report from market-research firm Kalorama Information expects the overall global market for drug development to exceed $105 billion by 2010, with outsourcing accounting for a healthy 40% of the market. As drug companies bolster their pipelines, clinical-services companies must rise to meet their needs. Companies’ internal teams and their outsourcing partners are taking steps to ensure that this growth in new research translates into value. Sponsor companies must find a suitable balance between staffing up their in-house resources to manage growth and outsourcing many of the components of their clinical research. The current increase in outsourcing indicates that sponsor companies are not ready to commit to adding in-house resources if increases in R&D activity are not sustainable. In the short term, it’s more efficient to outsource as much as possible. Number of New Clinical Trials Increasing According to Tufts, the top U.S. drug companies have increased the number of new clinical trials by more than 50% since 2002, signaling a possible resurgence in R&D productivity. Our experts weigh in on the challenges associated with this growth in clinical-trials activity. LAMMERS. During the past couple of years, Serono has witnessed an impressive increase in the number of clinical studies. This is related to both increased output from our own R&D organization and to our aggressive in-license strategy of products in clinical development in Phase I, II, and III. Obviously, more products have created the challenges of trying to best allocate our own resources to this plethora of trials and to decide which ones, or which functional activities, to outsource to CROs. Therefore, we worked to develop and implement an outsourcing strategy for clinical development, hired a director of outsourcing based in our headquarters in Geneva, and educated our own organization, both in clinical development and in executive management, on the value that such an outsourcing strategy could bring to Serono. GRAY. Valera has experienced a significant increase in clinical-trial activity. Some of the challenges we face include project prioritization, an increase in study timelines, and more rapid selection of CROs. Because of the increase in the company’s clinical trials, it is important for our clinical-research managers to work closely with our management team to prioritize our projects and ensure that all study activities occur in a timely manner. Since our company outsources many of its clinical-trial activities, we go through a CRO selection process for each trial. We need to choose our CROs and other outsourcing partners more rapidly but still efficiently. We do this by ensuring that our requests for proposals are complete and thorough, and we set practical timelines early in the trial process. DYER. There has been an increase in trial activity over the last few years. In accordance with that increase, we’ve increased our internal monitoring capacity by 30%. And we rely on outsourcing partners as well to accommodate this increase. BLANKSTEIN. I don’t believe Genzyme has witnessed a significant increase in the number of trials, but the indications we are now investigating do require larger trials and the more traditional Phase I, II, and III development pathway than some of the ultra-orphan indications to which we are accustomed. In orphan indications, often the phases can be combined because of the limited patient populations. The challenges are having the right resources available and gaining experience in new geographic areas — such as Eastern Europe, China, and India — to access patients. DINGIVAN. Since 2004, MedImmune has experienced a significant increase in clinical-trial activity. We have 15 clinical programs in various stages of development. Our main challenges have been securing enough talented clinical-research professionals to manage these programs and to sustain the level of product-development excellence we expect from ourselves. The time, resources, and effort required to conduct excellent clinical trials is substantially greater than when we had only a handful of programs in clinical development. Thompson. Our Phase I clinical-trial program for Reolysin has significantly expanded in the past year and we expect to continue the expansion into Phase II trials in 2006 and 2007. Rapid expansion creates challenges similar to those faced by all growing businesses and poses the questions: can we secure the financial resources and the human capital required to successfully increase our business opportunities? Appel. We are a new company that has just launched the first clinical trial for our first clinical entity. As we conduct this trial, we are planning subsequent trials for the entity as well as bringing a second entity to the clinic. If, as we anticipate, our initial agent validates the safety and efficacy of our novel delivery methodology then we plan to generate a large number of novel therapeutic agents to test in the clinic as rapidly as possible. What Sponsors want from a Clinical-Services Partner Choosing outsourcing partners can be time consuming but finding the right ones can make a significant difference in meeting timelines and other expectations. The experts describe what they look for in clinical-service partners. DYER. Like most other pharmaceutical companies, we want to partner with established service companies that have recognized expertise in the area of services we are outsourcing. We look at their expertise, the quality of their people, the quality of their ICH/GCP-compliant processes, and obviously their capacity to fulfill the work we wish to outsource to them. Previous experience and stability are also important. Many of our relationships span several years because of the length of the clinical-trial process. LAMMERS. First and foremost, we focus on a CRO’s capabilities in the functions that we are interested in using. Then, since the CRO team and especially the project manager are critical for the success of the project, we look at the background and experience of those individuals. Therapeutic area expertise is also of importance, especially in a highly specialized area such as oncology, which is a new but very active field for Serono. This is an area where we are building a broad pipeline and moving toward establishing a solid franchise. GRAY. In assessing a CRO’s capability to fill a specific need, we look for three general attributes. The first is a broad and general knowledge of the clinical-trial process. Small to midsize pharmaceutical companies, such as Valera, typically have limited resources. The CRO must bring to the table the expertise and foresight we require to move the program forward. Secondly, a CRO must be dependable. The ability to rely on a CRO to meet timelines, be accessible, and assist in bringing a clinical program to fruition is essential. Lastly, the cost incurred must be fair and sensible. Therefore, the CRO must be willing to propose reasonable and affordable budgetary proposals as well as negotiate the cost of a given service. Thompson. We look for a solid track record of success in managing similar clinical trials, experience in the treatment of specific cancers or with specific biologics, access to a patient base, and adherence and respect for company and regulatory requirements. Appel. Our first considerations are experience in the areas of patient care for the appropriate diagnosis and a history of successful clinical protocol executions, record keeping, and overall trial execution. This applies to study sites and other clinical partners. Patient accrual is a major consideration in our decision making. Naturally cost is a large determinant, however, cost is measured not just in dollars but in time to completion, quality of the documentation, and ease of execution. In our case, we are developing modified bacteria as live vaccines for the treatment of cancer, so the quality of patient care is of paramount importance. Our Phase I/II study currently in progress is the first time Listeria monocytogenes, a potentially pathogenic organism, is being used to treat cancer. Thus, the potential for adverse events clearly exists but cannot be well defined. As a result, we are extremely concerned that we recruit good physicians at quality sites who will not compromise our efforts through inappropriate treatment. BLANKSTEIN. Some of the more important aspects that partners need to have include global experience/presence, expertise in the indication, and a team who will be able to work well with our team to provide early input to activities that could impact the budget. DINGIVAN. Above all, we have to know that potential providers are true partners. Not only does this mean that they are skilled and able to perform the services for which they’ve been contracted, but they also have the courage to tell me, as the sponsor, what they need from me and how we can best work together to give the program the greatest chance for success. Too often, client-provider relationships are superior-subordinate in nature. Sponsors tell providers what they want; providers give it to them. Within a true partnership, the lines blur somewhat, and it’s the program’s goals that become the priority, not who works for whom. The Variety of Services that Sponsors Outsource Every sponsor company outsources some of its clinical work. The key is choosing the right services to contract out and which ones to keep. Our experts share their ideas on what processes to keep in house and when they prefer to use a partner. BLANKSTEIN. We outsource data management, clinical monitoring, medical writing, electronic data capture, ECG core labs, central lab services, and imaging. Appel. We currently are outsourcing everything as we move from a virtual biotech company to one with laboratories, personnel, infrastructure, and so on. We are at a stage where we are growing rapidly, and part of that growth involves creating some internal clinical capabilities. The specifics of this internal clinical capability are topics of discussion at this time. Our thoughts are to first bring monitoring and study coordination in house. DINGIVAN. Primarily clinical-trial management, such as site monitoring, data management, and IVRS, are the areas that we outsource when the demand of the program exceeds our internal capacity. This is mostly the case on larger, later-phase, or global trials. DYER. We outsource primarily operational activities, such as trial setup and monitoring, data management, statistical programming and reporting, central lab services, and medical writing. When we use IVRS for randomization, we outsource this as well. GRAY. We currently outsource several of our clinical needs, such as statistical, medical writing, data management, and monitoring services. Most often, Valera contracts services through several smaller vendors, as this has been an effective method of minimizing costs. In managing trials, we enjoy the flexibility of being able to choose niche vendors and bringing a great and varied team together for one common goal. But the management of the various vendors can sometimes pose a challenge in coordinating the activities and the timing of deliverables since the team is so interdependent. As the company continues to expand and grow and the size and number of our clinical trials increases, we may consider looking at individual CROs that offer comprehensive services. LAMMERS. Our outsourcing activities cover a wide variety of activities, but mostly we outsource trial monitoring, notably in up-and-coming territories such as Eastern Europe; data management and biostats, for example in the Phase IV arena in cooperation with our medical-affairs colleagues; and medical writing. Sponsors are keeping some functions in house There are some services our Forum experts say their companies will not outsource. It makes sense to keep core competencies in house, especially when they give them a competitive edge, while some tasks are more efficiently performed by a partner, as described by our Forum participants. DINGIVAN. For the most part, we retain project directorship, medical monitoring, medical writing, and biostatistics in house. We’ve identified these as significant core competencies, and we believe we have the best chance for success leveraging these expertises in this manner. GRAY. While we currently outsource many clinical-trial services, we prefer not to contract out protocol development and overall management of the trial. We believe that development of the protocol should originate from the sponsor company. We do currently outsource writing of the protocol to experienced medical writers; however, the thoughts and design behind the trial are developed by the Valera team. We also prefer not to outsource overall management of the clinical trial. We believe that it is important to use CROs to assist us in tasks such as site selection, monitoring, and data management; however, we believe that it is our responsibility to oversee the trial as a whole. As the sponsor of the trial, it is imperative that we stay informed of site progress, safety, and efficacy results; build relationships with our sites and investigators; and maintain a complete picture of the trial. Appel. We are currently outsourcing everything, however, we already have rejected very cost-effective overtures to work in countries in which we believed our intellectual property may be compromised or where we believed the standards of quality for patient care did not meet our requirements. LAMMERS. Clinical knowledge in a given therapeutic area is one of those core competencies that we believe we should build, and keep, in house. Both the regulatory agencies and the clinical investigators view us, as sponsors, as experts on our compounds and in the therapeutic area that we are active in, and we do not want to disappoint them. Quality management is another area where we feel in-house capabilities are critical since this group truly understands how we operate. Thompson. We don’t outsource every aspect of our business, but there is very little that we wouldn’t consider for outsourcing if we believed it would help us to expedite the development of Reolysin. DYER. We only outsource purely operational work. We keep Novartis’ strategic and scientific work, such as program and protocol design, in house. We consider these to be core competencies, and they are capabilities that we want to retain and further explore internally. Tweaking the Outsourcing Strategy If the only true constant is change, then it’s smart to always keep an eye out for what’s coming down the road. We asked our experts to project any planned changes to their clinical programs over the next five years. GRAY. As the company continues to grow, there will be increased reliance on experienced CROs to provide expertise and sufficient manpower to allow us to get trials completed. I still expect the internal managerial leadership coming from Valera on CRO-run clinical trials. Our clinical-research managers play a critical role in planning, accessing, and implementing this strategy and will increase their clinical responsibilities as our company continues to grow. I think it is important to realize that clinical research is a fluid process and change is a necessity in this business. LAMMERS. Our list of trials keeps growing and will continue to do so in the years ahead, especially since our hunger for more products and technologies has not yet been satisfied. Apart from internal growth, this will mean more outsourcing; and, therefore, we built up that outsourcing capability and experience during the last 12 months. DYER. We’re looking to decrease our overall outsourcing in data management and statistical reporting by building further internal capabilities in developing markets such as India. We’re staffing up to accomplish this goal. Appel. The outsourcing market is increasingly competitive as more people leave established companies and find profitable niches in the CRO market. While control of resources is desirable, future decisions will, in part, be based upon the cost and quality of available services. Thompson. As our clinical-trial program matures, we continually review ways to maximize our internal and external resources. From time to time, this may involve a reassessment of how we outsource and how much we outsource certain services. BLANKSTEIN. We, most likely, will outsource more over the next five years than we do currently. Shedding Light on Clinical-Trial Weaknesses The clinical-trial process is fraught with hurdles and obstacles. Aside from safety and efficacy issues, any systemic-related delay prevents therapies from getting to the customer and hampers the sponsor’s ability to generate a return on its investment. We asked our experts what weakness in the process they would like changed. Thompson. Biotechnology and pharmaceutical companies would like to see an expedited review of protocols by internal review boards (IRBs). The IRB system is being overwhelmed by a growing list of new agents and approaches, often directed against nonvalidated targets by nonvalidated approaches. The current system requires the sponsor companies to embark on a time-consuming process to educate each IRB about these new agents or targets. A centralized review system and more frequent meetings of IRBs would be positively viewed by the industry. LAMMERS. The weakest aspect of our industry’s clinical trials is patient recruitment — where to find the right patient for the right indication and for the right study. Also, educating the public at large about the value that we, as an industry, bring to society by developing newer, more efficacious, and safer drugs, and how they can help us by participating in clinical trials. For example, only about 8% of cancer patients take part in clinical trials. DYER. We need to become better at identifying the optimal clinical-trial sites that we work with. Obviously, a base requirement for any site that we would contract with for a trial is that it has to be qualified to do the work. Also, we want assurance as to the appropriate quality of execution. We have standard processes and procedures to rigorously adhere to these standards. Another important facet is to make sure the sites are able to recruit the appropriate patients for the trials in the allotted time period, so we can meet our overall timelines and bring our medications to patients as quickly and efficiently as possible. On the sponsor side, we can make improvements to feasibility assessments and understanding local timelines. Some countries can start clinical trials faster than others. We need to get better at identifying the different sites’ capabilities based on timeline requirements. BLANKSTEIN. Overall, the industry would benefit from improvements in the areas of IRB review, contracts, and site budgets. GRAY. One practice that needs improvement and is sometimes absent from the clinical-trial process is foresight. One can never underestimate the importance of being proactive and anticipating a potential bump in the road. I believe an essential indicator of good management of a clinical trial is having the foresight to envision the things that could become hurdles and having a contingency plan to keep things running smoothly and on track. It is inevitable that something will occur during the course of a clinical trial that is unexpected; and if there is an action plan for just this occasion, most potential problems can be avoided. For example, if a clinical-research manager encounters challenges in enrolling a particular patient population, a contingency plan of identifying potential back-up sites that have the ability to get up and running quickly could salvage the timelines for the study. In my personal experience, I recommend a team brainstorming session at the start of every trial, and possibly at interim points during the trial, to identify and prepare for potential issues as well as formulate adequate and acceptable resolutions. DINGIVAN. Measuring the actual benefit or ROI on initiatives to reduce development time or improve overall success would be beneficial, such as incorporating biomarkers or other translational medicine techniques into early-phase clinical trials. In the short term, some of these strategies can increase cost, and timelines, but the hope is that they will pay off in the broader view of drug-development cycle times or overall success rates. Appel. I don’t believe there is a single answer to this question. Different programs have different needs and different problems. Plenty of Challenges Our experts had a great deal to say about specific challenges in their clinical research programs. We asked them to speak to one of their toughest challenges. LAMMERS. Our greatest challenge is balancing the conduct of studies in those areas of most interest to the business, the United States and the European Union, with the need to go to developing countries in Asia and South America to find patients. Every region has its own list of investigators it would love to take part in clinical trials, but it is tough to please them all. So the choice is based on the need for speed since, next to quality, time to market is still the most critical factor in drug development. BLANKSTEIN. Patient recruitment and integrating teams to successfully manage large global trials are major challenges. DYER. We need to be pioneering drug-development solutions that will deliver innovative medicines to patients as fast and efficiently as possible. We need to be driving innovative approaches, such as increased use of modeling and simulation techniques to try to predict trial outcomes. Adaptive trial designs can be used, which allow for earlier safety and efficacy readouts involving fewer patients. Also, the field of biomarkers will help us to predict the safety and efficacy of a compound earlier in development. Changing the drug-development paradigm by using innovative approaches needs to be a key focus. For this goal to become a reality, we need to work with experts around the world to help define and obtain consensus on innovative approaches to development. We will need to adapt our operations to achieve the flexibility that these innovative approaches require. Appel. Our biggest challenges are anticipating the response of the FDA and devising a strategy and associated tactic to present high-quality data within the constraints of our immutable timelines and cost parameters. Designing a program for an oncology therapeutic based upon the first-in-man use of a modified pathogenic microorganism for a small biotech company is not easy. We want these data to be well-received by international regulators. And executing the trial within the time and cost constraints of a small, newly created biotech company requires an understanding of the methods and objectives as well as creative execution. Good science and good regulatory practices make this process very expensive and time consuming. Using our resources in ways that achieve our objectives in the most efficient manner, and which will be well-regarded by reviewers, requires us to sail in uncharted waters as we construct the boat. Thompson. Because we work with the reovirus, a new approach that has not yet received regulatory approval in the United States or Europe, we must collect and integrate data not normally required for other types of agents or approaches. For example, we must collect vast amounts of data related to viral shed for a product that exists naturally and ubiquitously in the environment. This simple lack of understanding or familiarity with these new types of approaches can create an additional burden for development-stage companies. GRAY. The biggest overall clinical-research challenge is getting the right CRO for the proposed study and making sure that the group can do the job in the designated time or earlier; do it within budget; and most importantly, produce high-quality work that results in the best possible clinical study. As a small business, we don’t have the luxury of a possible failed trial; we must be successful and use all the tools available to achieve success. All of our strategies revolve around ending up with a successful clinical trial. Barriers to Success Rarely, if ever, does clinical research go without a hitch. Our experts were open and honest when describing some of the toughest barriers they face when it comes to achieving their clinical objectives. GRAY. The greatest barriers to achieving our clinical-research objectives are the time to study start up, getting the right CRO for the study, and meeting budget constraints. Starting the study takes a lot of team work and coordination. Finding the right CRO that fits with the organization is a challenge usually overcome by team experience, bid assessment, and getting a feel for the CRO team. Budget constraints always play a key role in deciding which partner to choose, but budgets should not always be the main focus. I am a firm believer that putting innovative and clinically experienced people in the organization has allowed for success. Appel. Some of the considerations we need to accommodate are the large number of research efforts that limit the number of available sites in the United States and the disparity between academic medicine and industrial research. The latter frequently manifests as a lack of understanding of the available patient populations in the context of protocol requirements, as well as the time and resources required to provide the contracted data as a deliverable. For a small company such as ours, time is more than money; it can mean survival. A facility that claims to to see hundreds of patients with a specific indication annually but can only identify one patient a month who meets the protocol criteria, is a very bad site. It can mean that a study that might be conducted in months takes years, while the company continues to burn money month after month, with no progress to report to capital markets. BLANKSTEIN. Our biggest barrier is working efficiently with our global offices and CROs. Thompson. We face the same barriers as other biotech and pharma companies — for example, access to patients, access to trial sites, and review times by IRBs. DYER. The greatest barrier in clinical trials today is execution. We have good strategies and good planning. Novartis achieves good timelines compared with the rest of the industry, and any improvements will have a direct and measurable impact on the value created for patients, customers, and companies. LAMMERS. A big barrier to success is building a understanding and buy-in to one consolidated drug-development strategy in a global company with a global development organization. And at the same time, gain consensus among different business/commercial organizations and the various interests and needs that have to be served across the globe. Choosing Global Clinical-Trial Partners Many companies are increasing the number of trials they are conducting outside of the United States. When a trial is on a global scale it often requires a new outsourcing approach to selecting the right partners. Here’s what our experts had to say about choosing partners for global trials. BLANKSTEIN. We look for partners who have long-term experience in a particular country. Partners should know the regulatory processes in all countries and how to obtain approvals. They must know the investigators and have processes that enable them to communicate globally with their teams. They also must have a project team leader with global experience. LAMMERS. To find patients, all the bigger companies will have to go outside the United States. For example, we are running several studies in Russia, and using a Russian CRO for trial monitoring has helped us achieve our recruitment goals. In addition, many of the CRAs in Russia are very well qualified, since most are physicians. They are very interested in the study protocol and making sure that the study runs smoothly. GRAY. We want to ensure that the CRO we hire to manage our ex-U.S. trials is very knowledgeable about the country. We are relying on this CRO to help us identify sites and leaders in the area, obtain regulatory approvals according to local and/or country regulations, identify the areas for successful patient recruitment, and execute a successful clinical trial. We also look for a CRO that will act as a true partner. If we are conducting a trial in the United States as well as outside the United States, and are relying on the CRO to manage the ex-U.S. portion of the trial, it is critical for us to work together and be consistent. DYER. Most of our trials are global. We need partners that have an established presence and access to high-quality operations in the geographic areas where we are conducting trials. So we look for partners that either have their own offices in the countries where we want to execute the trial or have established relationships with local providers. Appel. We look for the same things in global partners that we seek in domestic partners: demonstrated quality in the execution of trials, a good track record, the ability to withstand inquiry and investigation, and competitive cost. In addition, we look for the ability to comply with ICH treaties so the resultant study is applicable in all our regulatory filings. Maximizing Partnership Performance Is there a key to working with outsourcing partners and maximizing the probability of a successful outcome? Our experts provide some valuable insights into what makes a successful relationship. DYER. Establishing clear expectations up front for both parties is key. This includes goals, deliverables, and performance metrics, so everyone understands what each party’s contribution will be. Flexibility and commitment by both parties is important in dealing with unforeseen obstacles. Committing to these strategies results in a true partnership and a joint commitment to achieve objectives. Thompson. The key to any successful working relationship is managing expectations on both sides so that realistic objectives can be set and then achieved. GRAY. A successful outsourcing experience is the ultimate goal of the sponsor and the CRO. For our clinical-research managers, the task of constructing and managing a seamless and cohesive team is one that I find quite challenging. This challenge is further complicated when working with several vendors on one particular trial. Fundamentally, two key elements — collaboration and communication — must be present for a sponsor/CRO team to be successful. The first key element is collaboration. Collaboration, simply put, is the act of working together with one or more people to achieve a common goal. As clear-cut as the concept may sound, I have often witnessed team members working independent of the team and losing sight of the big picture. The second key element in a successful outsourcing experience is communication. It has been my experience that productive and frequent communications are the underpinning of a team. Our clinical-research managers are responsible for facilitating these communications, however, it is the entire team’s responsibility to contribute and participate. A successful outsourcing experience derives from a team that uses effective communications and collaborations to achieve the common goal of completing a quality clinical trial within the timeline allotted. I do not believe this can be accomplished without successfully working as a team with our vendors. LAMMERS. The first step is having an in-depth understanding of the clinical-operations business: how to best organize clinical trials, what resources are available in house to make the trial happen, and so on. The next step is setting very clear and transparent goals and objectives for outsourcing partners, accompanied by detailed contracts to avoid any misunderstandings later in the project. Finally, having strong internal managers to oversee the CROs is a must; leaving everything up to the CRO is often a recipe for disaster. appel. We have been very careful with the vendors we have chosen and have not had any problems of consequence. We look for experience and track record, and we shop around extensively. While we are working offshore, we do not consider countries where we are not comfortable, and we research potential candidate companies, their references, and published works. Thus far, we have not experienced any problems outside of the ordinary difficulties one encounters in conducting clinical trials. BLANKSTEIN. We highly value honesty and low staff turnover. And, in case there is unexpected staff turnover, the CRO needs to have a plan to ensure a smooth transition. If the CRO is honest and has depth on the bench, the project can continue to move toward a successful outcome. Best Practices for Service Providers No two outsourcing partners are alike, but one thing is clear: they are all expected to execute. One way to maintain consistency and quality is to share best practices. Our experts outline some of the best practices they would like outsourcing partners adopt. BLANKSTEIN. Outsourcing partners need to provide realistic budgets and timelines during the bidding stage. They have an experienced staff. And they need to be able to anticipate problems early in the program and provide solutions. LAMMERS. Best practices include having an interest in trying to understand the client’s organization, governance, and decision-making process; a willingness to be completely open about its own organization’s strengths and weaknesses; be daring enough to say something is not an area of expertise; and communication. Our lives, our industry, and the success of all of our companies is built on the two most important basics of interaction: information and communications. Appel. Some advice for service providers is to be conservative in time and pass-through cost projections; be realistic; and manage expectations. Budgets are not exercises in creative writing. Budgets that are too complex and give the appearance of redundant billing are an immediate red flag, and we usually end the dialogue right there. Also, vendors need to understand the customer’s needs and internal capabilities; don’t provide less than the sponsor needs and don’t add on things the company can do for itself. DYER. Good outsourcing partners should have flexibility and high-quality project managers in place to oversee the relationships and assure a rapid resolution of any arising issues. They should be clear about what they can commit to, and they should deliver on those commitments. Also, consistency of staff, with low turnover on the team, is important for good interactions between the partner and sponsor. GRAY. Although this particular topic could elicit many responses based on an individual’s experience with a CRO, in general there are three best practices I believe could benefit outsourcing partners as well as pharmaceutical companies. The most important practice that outsourcers should adopt is departmental cross training. This would require key representatives from various departments, such as clinical, data management, regulatory, research and development, and even manufacturing, to learn what the other does and gain knowledge and even respect for the other’s responsibilities. Consequently, logical and realistic decisions will be made and be based on knowledge of what each department’s responsibilities entail. Another best practice that, in my experience, is lacking in the outsourcing community is researching disease indications that are the topic of the clinical trial they are working or bidding on. This practice should not be limited to clinical monitors or project managers, but should extend to laboratory vendors, data managers, and even data-entry personnel. There tends to be a misconception that such specialty areas do not require a working knowledge of the disease because their job focus is narrow. But we have found that lab-value trends as well as adverse-event trends could have been identified sooner had the representative been properly trained in the disease indication and population. Lastly, from an administrative standpoint, a best practice that I believe would aid in trial management would be a formal, standardized, interim method of updating the sponsor on the progress of the trial. Our team often has had to solicit updates from the outsourcing partner. Furthermore, these updates have not always been as comprehensive and frequent as we would like. A sponsor/CRO agreement of frequency and a standardized method of delivery encompassing updates for all services contracted would be of great assistance in trial management. Thompson. Outsourcing partners should exhibit experience and responsiveness, with more emphasis on underpromising and overdelivering. Technology’s Role in Clinical Research Technologies, such as EDC, IVRS, and ePRO are meant to improve the process. Our experts share their thoughts on the role of technology, and its impact in shaping the future of clinical research. DINGIVAN. As an industry, we can be optimistic about the promise of these technologies to make trials faster and more affordable. Only recently, however, has this become a reality. There are many obstacles to fully implement technology solutions, not the least of which are related to infrastructure and personnel. But as the clinical-research community becomes more comfortable with technology — and the products get better and easier to use — we’re beginning to realize optimal use of these tools and benefit from their advances. BLANKSTEIN. I believe electronic solutions do indeed improve the process. But there are questions related to access for the investigator sites and a company’s ability and willingness to allow its partners to share information on their servers. Separate, secure sites must be established so all involved with a trial have access to information. Appel. I believe that some of the new technologies, such as EDC, are improving the process. However, in this context, I would quote Dr. William Osler, the first physician at Johns Hopkins: “Be not the first physician to try a new remedy, nor the last.” DYER. All Novartis data management performed in house by our data-management department uses EDC. Our system has been in place for five years, and we’ve experienced significant increases in efficiency, quality, and speed through the use of EDC. IVRS allows us to use our drug supply more efficiently through regional randomization rather than per center. As we go forward, new approaches, such as adaptive trial design in studies and more trials investigating the use of customized medicines, will require us to have a more flexible approach to delivering supplies to individual patients and groups of patients. When we’re talking about modeling and simulation of trials, we need to be able to combine data from different sources, both internally and externally, to help predict trial outcomes. Systems that are ambidextrous in their communications abilities will really help. Technology is key as we move forward. GRAY. In my experience, technologies such as EDC and IVRS are improving the clinical-trial process, but there also is room for improvement. The number of clinical trials is growing significantly, which has increased the need for well-organized, efficient trials. EDC has reduced CRF completion and collection times, therefore producing quicker access to results for sponsor companies. But EDC, which also allows for all involved parties to have access to the CRF data — sponsor, CRO, data management — can lead to an increase in queries or repeated queries. This counteracts the efficiency of EDC. I believe that IVRS technology has improved the clinical-trial process by providing more accurate and immediate access to trial information, such as randomization of eligible subjects, drug accountability, and subject questionnaires. With IVRS, we no longer have to wait until we receive the monitor report to know which subjects were randomized or whether a screen failed. We also get faster access to information about those subjects, such as reason for failure, current dose of study or comparator medication when randomized, lab results, and so on. IVRS also has helped improve the results of subject questionnaires by reducing the amount of lost data. When a subject calls into a telephone system to answer questions, the results are recorded and transmitted to the applicable parties. We no longer have to be concerned that subjects will lose their study diaries, therefore losing part of the study results. LAMMERS. Technology certainly helps. Serono is an industry leader in the implementation of EDC, with 70% of our clinical trials currently using the technology. IVRS has helped tremendously in the recruitment and randomization process; and with more and more trials incorporating patient reported outcomes, ePRO is rising in importance as well. Many companies are struggling with implementing such technologies. Based on our experience, it all comes down to several factors for success: dedicated, tech-savvy professionals; buy-in and full support from senior management; clear vision of where the company would like to get to at the end of the implementation process; metrics for every step in the process; a positive attitude toward, and trust in, the own organization; and the people to make it happen. PharmaLinx LLC, publisher of the VIEW, welcomes comments about this article. E-mail us at [email protected]. Our lives, our industry, and the success of all of our companies are built on the two most important basics of interaction: information and communication. Outsourcing partners have to understand the client’s organization, governance, and decision-making processes; be willing to be completely open about their own organization’s strengths and weaknesses; and be daring enough to say something is not an area of expertise. Paul Lammers Serono The most important practice that outsourcers should adopt is departmental cross-training. This would require key representatives from various departments such as — clinical, data management, regulatory, research and development, and even manufacturing — to learn what the other does and gain knowledge and even respect for the other’s responsibilities. William Gray Valera Pharmaceuticals The indications we are now investigating require larger trials and the more traditional Phase I, II, III development pathway than some of the ultra-orphan indications where Phases could be combined due to the limited patient populations. The challenges are having the right resources available. Larry Blankstein Genzyme PharmaVOICE Clinical-Research Survey A May 2006 survey of biopharmaceutical companies about outsourcing clinical services revealed … 86% said their outsourcing budgets increased over the past year 84% conduct trials outside the United States 44% work with five or fewer outsourcing partners 38% outsource 91% or more of their clinical-services work 26% expect budget increases of 31% to 60% in the next year Most common services outsourced by sponsor companies (percent of respondents who say they outsource each service) 1. Monitoring — 84% 2. Trial Management — 80% 3. Site Recruitment — 74% 4. Patient Recruitment — 74% 5. Data Management — 72% 6. Report Writing — 56% 7. Regulatory Submission — 36% 8. Regulatory Compliance — 32% 9. Protocol Design — 28% Ex-U.S. countries/regions that pose the best opportunities for clinical-trial outsourcing 1. India 2. Eastern Europe (non-E.U.) 3. Russia/Ukraine 4. China 5. Mexico/Latin America Top Clinical Technologies Used (as selected by survey participants) 1. IVRS 2. ePRO 3. EDC 4. CTMS 5. eDiaries Source; PharmaVOICE, Titusville, N.J. For more information, visit pharmavoice.com. Note: Total respondents: 84 — pharmaceutical 65.7%; biotechnology 13.4%; biopharmaceutical/biologics 9%; and other (including device manufacturers, outsourcing suppliers, brand consultants, and CROs) 11.9%. Over the past few years, we’ve increased our internal monitoring capacity by 30% to cope with the increase in new clinical trials. We outsource primarily operational activities, such as trial setup and monitoring, data management, statistical programming and reporting, central lab services, and medical writing. Nora Dyer Novartis Pharmaceuticals We have to know that potential providers are true partners. Not only does this mean that they are skilled and able to perform the services for which they’ve been contracted, but they must also ha e the courage to tell me what they need and how we can best work together to give the program the greatest chance for success. Dr. Christine Dingivan MedImmune Fast Facts About 20% of self-originated new drugs that enter clinical testing receive U.S. marketing approval. Top U.S. drug companies have increased the number of new clinical trials by more than 50% since 2002. Source: Kalorama Information, New York. For more information, visit kaloramainformation.com. Drug companies stand to lose between $600,000 and $8 million each day clinical trials delay a drug’s development and launch. Source: Cutting Edge Information, Durham, N.C. For more information, visit cuttingedgeinfo.com. Dr. Brad Thompson Oncolytics Biotech We don’t outsource every aspect of our business, but there is very little that we wouldn’t consider for outsourcing if we believed it would help us to expedite the development of our product. Thought Leaders Roni Appel. President, CEO, and Chief Financial Officer, Advaxis Inc., North Brunswick, N.J.; Advaxis is a biotechnology company that uses live, genetically modified Listeria monocytogenes to treat cancers, infectious disease, and problems of the immune system. For more information, visit advaxis.com. Larry Blankstein. Senior Director of Clinical Research, Genzyme Corp., Cambridge, Mass.; Genzyme’s products and services are focused on rare inherited disorders, kidney disease, orthopedics, transplant and immune disease, cancer, and diagnostic testing. For more information, visit genzyme.com. (Mr. Blankstein is serving as chair of the clinical-research track for the upcoming Drug Information Association (DIA) Annual Meeting. DIA does not advance any single position, therefore Mr. Blankstein’s responses are based on his personal and professional experiences.) Christine A. Dingivan, M.D. VP, Clinical Research and Operations, MedImmune Inc., Gaithersburg, Md.; MedImmune is focused on the areas of infectious diseases, cancer, and inflammatory diseases. For more information, visit medimmune.com. Nora Dyer. Global Head of Clinical Development Operations, Novartis Pharmaceuticals, Basel, Switzerland; Novartis is a world leader in medicines to protect health, cure disease, and improve well-being. For more information, visit novartis.com. William Gray. Senior Director of Regulatory Affairs, Valera Pharmaceuticals, Cranbury, N.J.; Valera focuses on developing and marketing therapeutics for urology and endocrinology specialties, as well as advancing drug delivery with its Hydron Implant Technology. For more information, visit valerapharma.com. Paul Lammers. Chief Medical Officer, Serono Inc., Rockland, Mass.; Serono is a global biotechnology company with eight products on the market in four therapeutic areas and currently more than 25 ongoing preclinical and clinical-development projects. For more information, visit serono.com. Brad Thompson, Ph.D. Chairman, President, and CEO, Oncolytics Biotech Inc., Calgary, Canada; Oncolytics focuses on the discovery and development of pharmaceutical products for the treatment of a wide variety of human cancers. For more information, visit oncolyticsbiotech.com.
