While the U.S. Food and Drug Administration has accelerated its review and approval of new medicines, drug developers’ increased focus on complex diseases, such as cancer and neurological disorders, as well as disorders for which there are few effective therapies, has resulted in longer clinical development times. According to the Outlook 2009 report from Tufts Center for the Study of Drug Development (CSDD), the average time for the FDA to approve new drugs has declined to about 13 months in recent years; however, when coupled with a more lengthy clinical-trial process, the overall amount of time needed for drug development and approval continues to average about 8 1/2 years. Still, Tufts CSDD Director Kenneth Kaitin notes, drug developers are making progress in the effort to accelerate the clinical process, adopting strategies such as improved project management and portfolio decision-making, expanded reliance on partnerships and licensing arrangements, and increased use of surrogate endpoints and adaptive clinical trials. Technologies for Transparency Electronic documentation and monitoring tools have become a critical component of clinical operations management, and as they continue to evolve, these technologies have the potential to do more than improve organization and dissemination of data. “Electronic records eliminate a lot of extra work; they avoid errors in transcription and they facilitate real-time collection and retrieval of data," says James Baker Jr., M.D., CEO, founder, and executive chairman of NanoBio. “This not only helps in clinical-trial management, but may even help performance; data can be quickly reviewed as collected, and if there are issues, the trial can even be changed." These technologies also have resulted in increased transparency, which helps protect clinical studies from fraud and improves the accuracy and believability of the data collected. “The data collected by these real-time electronic systems are auditable, accurate, and believable, so it’s easier to trust the answers revealed from the trial," says Roger Garceau, M.D., FAAP, senior VP and chief medical officer for NPS Pharmaceuticals. Nancy Boman, M.D., Ph.D., VP, clinical development and regulatory affairs, for Acucela, cites electronic tracking documents as another technology that provides increased transparency in clinical operations. “There are now better tracking tools to determine if the milestones laid out are actually being met," Dr. Boman says. “There is better accountability for what the investigators have done and what the sponsors have done. The industry is able to codify its needs into clinical development plans, regulatory strategy documents, and advanced marketing plans." Arete Therapeutics’ Chief Medical Officer Randall Whitcomb, M.D., credits interactive voice response systems (IVRS) that manage laboratory, patient, and supply activities with providing another layer of transparency. “We can track patients in screening and randomization in real time, monitor screened patients for inclusion and failure rates, and provide precise quantities of clinical supplies," Dr. Whitcomb says. “This facilitates a just-in-time approach using up-to-the-minute information that eliminates waste and the cost and inconvenience of disposal. We can also track patient enrollment trends and, if needed, make necessary modifications to the number of sites we will need to achieve enrollment goals more quickly and efficiently." As the use of electronic data capture (EDC) systems increasingly becomes mainstream in clinical research, replacing the use of paper CRFs, much focus has been placed on the revolutionary impact this technology has had on the role of clinical data managers. However, Ron Rubinstein of Medidata says one could argue that an even larger, yet seldom discussed paradigm shift has taken place with respect to the responsibilities of another key player on the clinical development team: the clinical monitor or clinical research associate (CRA). Mr. Rubinstein says EDC is playing such an increasingly important role in automating mundane activities, in established areas such as data and source document verification, that monitors can now focus on areas where the human touch is necessary to drive investigational sites’ clinical success. (To read more about how EDC has changed the game, please turn to page 24.) While these technologies are pretty well entrenched on the clinical side, the regulatory side has yet to fully embrace electronic documentation. Clinical operations executives agree that progress has been made on this front, but that more needs to be done to get regulators and drug developers on the same electronic page. “We need to capitalize on the electronic revolution while keeping our quality standards at a level that ensures the data are believable and can fully replace the complete paper or mixed paper/electronic capture of what happens at the investigator site," says Luc Truyen, M.D., Ph.D., senior VP and head of global clinical operations, Johnson & Johnson Pharmaceutical Research & Development. “Investigator acceptance and adequate training need to go hand in hand to make the electronic system as efficient and accessible as possible." Dr. Truyen adds that recent developments, such as CDISC as a common data language and method of reporting, have been of great benefit in the dialogue between sponsors and the agencies on electronic documentation and submissions. Mark Weinstein of BioClinica agrees that the clinical research process will become more efficient as all stakeholders collectively support not only the development of standards but widespread adoption and implementation. He says the time has come to use technology smarter; the current tools are available to provide a comprehensive vision to create clean clinical data faster and more efficiently right now. Supporting the vision requires people who have experience with clinical trials and expertise with the specific technologies that will be used. (To read more about how standards and their implementation can improve the development process, please turn to page 16.) Broader CRO Horizons There is no disputing the essential role that contract research organizations (CROs) continue to play in clinical development. According to Tufts CSDD, contract clinical services presently account for more than 17% of total drug development spending, and future demand for CRO services is expected to grow by more than 15% annually, outpacing overall spending on global drug development. This projection reflects pharma’s increasing reliance on contract providers to provide added capacity, more flexibility, and greater efficiency in the face of increasingly large, complex global clinical trials. Things may look rosy for the long-term future of CROs, but experts say the sector is facing the same short-term economic challenges as the overall pharma industry in the current downturn. “I believe that CROs are hurting for business and need to work harder to cater to pharma’s requirements and remain competitive in terms of services and costs," Dr. Boman says. “Pharma is working more closely with CROs to determine where some functions can be brought in-house to save costs, and I would think this is hurting CRO business." Lawrence Reiter, Ph.D., of Criterium contends that a drive toward innovation should remain strong — in good times or bad. Investment in pharmaceutical research and development needs to continue; life-saving drugs are vitally important to the future of the industry and, more importantly, to the patients who are in need of novel therapies. Dr. Reiter notes that the economy will eventually rebound, and because it can happen quickly, companies that become too lean in terms of headcount may not be able to compete if they do not have the right resources in place, meaning properly trained clinical staff members ready to do the work. (To read more about why maintaining clinical operations in a downward economy is good business, please turn to page 18.) Dr. Garceau observes that as more pharma and biotech companies put the brakes on clinical trials in an effort to curb spending, some CROs are becoming more reluctant to follow the traditional business model of work-for-pay, and instead are looking for more money up front. “With so many companies pulling back their business, some CROs are realizing the increased risk of doing work in advance of getting paid," he says. “In their contracts, CROs are explicitly outlining milestones and associated payments — they are paying much more attention to these details when dealing with smaller biopharma firms." “I think most businesses have taken a greater interest in ensuring the financial stability of the organizations they are relying on as partners," agrees Mitchell Katz, Ph.D., VP of global clinical and business operations at Eisai Medical Research. Even as some companies become more cautious in their business dealings, others are using the economic downturn to reach out to a broader customer base. According to clinical operations leaders, smaller and midsized biopharma companies are now receiving more competitive bids from a wider range of CROs, including larger firms that traditionally focused on partnerships with big pharma companies. “Before the economic downturn, many of the larger CROs were not as forthcoming to small companies; now they’re much more open to interact with us," Dr. Baker notes. “Certainly with a more competitive landscape, we’re getting more bids, and I think companies are looking hard at their cost structures. Given the cost of drug development, this is important." Dr. Whitcomb observes that recent wave of consolidation in the pharma industry has provided another incentive for CROs to reach out to small and midsized companies to expand their market. “This benefits a company such as Arete; we have greater access to and a stronger voice with midsized and large CROs," he notes. “CROs realize the need to maintain strong relationships with their sponsors, and that their future depends on their reputation." In the current environment, CROs also may have more of an opportunity to make inroads at companies that traditionally work with only a few preferred service providers. Dr. Truyen notes that J&J has a number of preferred CRO partners that together offer a certain level of business — typically 25% to 30% of its overall R&D activities — in exchange for an economically beneficial pricing arrangement. “This does not mean, however, that for certain highly specific projects we won’t go outside to a partner that has the technology and know-how to answer our needs quickly, and in the best and most efficient way," he adds. As is often the case in trying economic circumstances, the ability to remain flexible can mean the difference between survival and failure for CROs. “I would say small CROs, and especially CROs from emerging countries, have a chance to use this crisis to grow their businesses," says Christoph Schnorr, senior VP, global clinical operations, for Merck Serono. “In the end, what counts is agility, and in this environment, both small and large CROs have to be more flexible then they were in the past. “I think the economic situation has forced many CROs to change their traditional business model from being a simple service provider to becoming a real partner; we are working with some preferred providers that are willing to commit to more tangible outcomes, rather than merely providing services for fees," he continues. “Overall more complex services require more advanced business models, and I think there’s a huge opportunity for CROs to use the economic crisis to adopt those models. Those that stay in that old paradigm and keep that old business model will have a hard time in the future." Stephen Cottrell of inVentiv Clinical Solutions agrees that the growing popularity of flexible service providers has greatly increased the comfort level among sponsors; this model allows the sponsor to set the level of control for each project. Today, he says, there are many viable alternatives to the traditional model that ensure that both flexibility and quality are delivered. The results are a reduction in the sponsor’s infrastructure — systems, processes, management — and improved margin contribution and efficiency gains. (To learn more about the importance of building a service model to fit a sponsor’s needs, please turn to page 22.) Dr. Katz describes Eisai’s approach to its two main CRO partnerships as outsourcing by program rather than by project. “We like to say the ‘CRO is us,’" he says. “The way we live this is by bringing the CRO in during the early stages and making sure our relationship is collaborative even in the development of the protocol so that their people are engaged in making the program a success from the start. Everyone then has an investment in seeing the program succeed." The Global View Drug developers continue to globalize their preclinical and clinical development activities to cut costs, overcome local capacity constraints, and expand their presence in emerging markets. According to Tufts CSDD, within the next three years, major sponsors project that up to 65% of FDA-regulated clinical trials will be conducted outside the United States — primarily in Central and Eastern Europe, Latin America, India, and Asia — due to economic advantages and ready access to well-trained physicians and large numbers of treatment-naive patients. The continued standardization of regulatory requirements across various global agencies also has made global trials easier to manage. But some clinical operations leaders perceive globalization of trials as a double-edged sword. “I think one of the biggest challenges in both the design and conduct of a global trial is factoring in the current standard of medical care, healthcare implementation, and data collection procedures for each specific country," Dr. Whitcomb says. “Another challenge is to ensure that the patients enrolled in the sponsor’s clinical trial mirror what will be needed for registration in the United States." “Understanding the ever-changing regulatory requirements in different regions demands a level of awareness and ability to assess what actions need to be taken to respond," Dr. Katz adds. “Other challenges are the logistical nature of getting drugs and samples in and out of the country and the existing standard of care in the region. Additionally, we have to manage the timelines and meet the expectations of the regulatory authorities." Mr. Schnorr, for example notes that in China, it takes one year from submitting a protocol to get approval to run the clinical trial. “If the timeline is not factored into the planning, the sponsor and CRO can end up with desynchronized clinical trials in different sites and different regions," he warns. “Planning involves an intelligent selection of the right countries and the right populations. And then, of course, this has to be combined with the legal requirements and regulations to get the trial synchronized." Most clinical executives agree on the importance of conducting trials in countries where the people involved will ultimately benefit from the resulting medicines. Dr. Garceau raises the example of tuberculosis, which is becoming more prevalent in developing countries. “Part of selecting where trials are based is determined by the greatest patient population, but we also have to be able to translate the study to multiple local medical practices," he notes. Site selection is critical to the success of any trial in any region; however, the right metrics must be used to evaluate site performance, and the trick is to identify high performers in advance, according to Bill Gwinn of i3 Pharma Informatics. Metrics offer a way to predict success, and the best ones use disease prevalence. Previously, Mr. Gwinn stated that sites should be located in high-prevalence zones, which is a “fish where the fish are" philosophy. The new idea is to go inside the walls of individual investigators to see if the specific practices have the patients. (To learn more about how metrics can be used to predict the success of clinical trials, please turn to page 20.) In its ethical code of conduct, J&J includes the statement, “We will help ensure access to our products in the communities where we develop them." “I think this is an important cornerstone for a productive collaboration with the countries, their thought leadership, government, and so on," Dr. Truyen says. “We see global trials as not just a means to conduct studies cheaper or faster, but as ultimately going where the medical need is and how our new product, whether a pharmaceutical or device, meets that need. Otherwise there’s no point in going to the country." Dr. Truyen adds that it will be tough to build trust in some regions if the company isn’t careful to take the needs of the community into account. “This has to be a two-way street, because otherwise, in the long run, the collaboration will not be effective for anybody," he adds. “A company may have a quick win in a region by getting patients in quicker, but if it is not seen as doing the right thing for the community, the next trial will be looked at very differently." A Standard for Protocols Despite use of adaptive trials, improved project management, and increased reliance on global partners, the cost of drug development remains stubbornly high, due in part to growing protocol design complexity. Drug developers are taking a closer look at protocol design as a way to achieve faster timelines, reduce costs, and deliver quality submissions. Rising numbers of protocol amendments, difficulties in patient recruitment and retention, and a high number of complaints filed against investigative sites for protocol noncompliance are driving pharma to find new ways to balance the scientific and operational objectives of protocol design. “It is possible to design a scientifically pristine trial with no possibility of actually executing it operationally," Dr. Whitcomb observes. “Biotech and pharmaceutical companies need to design trials to evaluate the most important characteristics of a drug while ensuring that there is a practical way to complete patient enrollment and implement data collection and analysis. To be successful, the clinical-trial protocols must be operational." Some pharma companies have put specific steps in place to ensure close collaboration between the scientific and operations teams. “In pursuing a collaborative approach between the strategic development plan and the clinical protocol, we’ve built in a step that we call a concept sheet, which is jointly owned by science and operations," Mr. Schnorr says. “Whenever we are reviewing protocols together, we take into account if the protocol is feasible and whether it enables innovative scientific approaches. This is an up-front investment that pays off at the end." Clinical operations executives also are examining ways in which to weed out unnecessary or duplicative procedures from existing protocols. According to Dr. Truyen, J&JPRD has instituted Project OPERA (Operational Effectiveness in Research) to examine the company’s protocols and determine whether the data points being collected contribute to answering the protocol’s central question. “With our clinical colleagues, we’ve started to ask whether all of the procedures need to be part of the protocol," he says. “For example, is a second height measurement or a fourth EKG at a particular date really necessary? These data points do not contribute to the actual answer to the clinical question, they just contribute to the cost and complexity." Eisai also is working to standardize its protocols. “By having a standardized way to capture information, we can be more consistent with our trials," Dr. Katz says. “Of course, there are times when customization is required, but when we start from one standard, we are able to note why a decision was made to modify an element of the protocol. This ensures nothing was overlooked and the scientific and operational objectives are aligned from the beginning." In addition, Dr. Garceau believes there is a third part of protocol design that is often overlooked by pharma companies. “First is developing a protocol that will answer a specific scientific question; second is picking a population that meets the study attributes," Dr. Garceau says. “The third part is the development of a medically meaningful treatment algorithm for the patient and the physician. When I start to consider a protocol design, I always start by thinking what the disease is and how patients are treated. It’s important to understand the disease and the patient flow within the disease, then try to picture where the drug fits into that process." Still Wanting for Patients Patient recruitment and retention remains a thorny problem for most drug developers. According to a recent Cutting Edge Information study, the ability to deliver patients is one of the key qualities sponsor companies look for in a CRO partner. (For more on the Cutting Edge study, please see box titled: The CRO as Partner.) Executives agree that the one question from potential clinical-trial participants that companies should be able to answer convincingly is: what’s in it for them. According to Mr. Schnorr, companies need to start raising that question from protocol development onward. “This approach can attract more patients, though of course it’s still a challenging task," he says. The smallest considerations can help with patient retention. “We have to view the process from the perspective of the patients — the little things like getting to the hospital or to the doctor, making sure there are parking spaces, things like this," Mr. Schnorr says. “Believe me, if you have a 78-year-old Parkinson’s patient, and you ask that patient to be at the hospital by 7 a.m., and the investigations last until 5 p.m., it’s very hard to get the patient and his or her relatives involved and enrolled. “If we invest a little bit more to make the life of the patient a little bit easier, it will pay off at the end of the day," he continues. Dr. Truyen says while patient recruitment can vary significantly across therapeutic areas and indications, there are some steps that can improve the odds of success across the board. “The first thing to do is encourage subjects to view the trial as a partnership," he notes. “While they may or may not benefit directly from the study, they need to believe they are contributing to the greater good." Even as the Internet has made clinical-trial information more accessible to patients through postings on patient advocacy Websites and government-sponsored databases, some experts believe these tools don’t necessarily translate to actual patients entering trials. “Electronic means of recruitment will continue to evolve," Dr. Baker says. “One method that sponsors may try is to search out people on the Web — not in a commercial or predatory way, but through patient care organizations. For example, the Cystic Fibrosis Foundation has done a very good job of organizing patient groups and providing information about clinical trials; we’re going to see more of these types of activities in the future." Dr. Garceau agrees that patient advocacy will continue to play an important role in patient recruitment. “Patients are the best advocates within the healthcare system to drive the research for new therapies, to drive for those therapies to be paid for, and to drive for those therapies to be put into their physicians’ treatment armature," he says. “We’re working with advocacy groups for hypoparathyroidism and gastric disease asking, how do we help patients?" The flip side of the recruitment challenge is keeping the patients from dropping out of the trial before it ends. “Often one of the biggest difficulties in our datasets is missing data — the things we weren’t able to measure because the patient didn’t come back — and how that missing data skews the trial results, which is of course a valid scientific/regulatory question," Dr. Truyen notes. While things like side effects and complicated procedures can prompt patients to withdraw, executives say there are ways to encourage patients to stick it out. Tools such as e-diaries and cellphone reminder calls help to keep patients on track with their medication regimens and other required tasks, and can tip off companies as to when a patient might be slipping away from the protocol. “Being able to see real-time data through new technologies has helped us identify when interventions might be needed to ensure retention," observes Dr. Katz. “I think there is a place for patient motivation and retention tools, mainly in those trials where there are very long-term outcomes," Dr. Truyen says. “Patient motivation and retention tools, which can be as simple as a leaflet with a current Webpage access update or even a Facebook group, could be valuable." Dr. Baker singles out the cellphone as an invaluable tool in a clinical trial. “Being able to contact people to reinforce what’s going on in the trial has a remarkably positive effect on participation," he observes. “There are some people who are never going to follow up for whatever reason, but for people who just might forget and then are embarrassed to come in later, a cellphone has helped with retention." Dr. Garceau believes that sometimes a retention tool is as simple as reminding patients why they agreed to participate in the trial in the first place. “There are so many things we can do during a trial to help remind patients about the benefits and the risks, and we need to provide this balance," he says. “Our aim over the long term is to keep patients motivated so they understand what they’re trying to do for themselves, for the other patients, and for future generations." Alicia Pouncey, MEd, of Aureus Research Consultants contends that to ensure the success of a trial, enhance patient participation and retention, and improve protocol design, there is a need for better training, especially around Good Clinical Practice (GCP). She says a better training approach would be to design engaging educational-strategies via protocol-simulation so that GCP is integrated into teaching protocol requirements. Expanding these types of targeted-training techniques and pairing them with evolving technologies, such as medical simulation, she believes will further meaningful learning opportunities. (To learn more about new training methods involving simulation tools, please turn to page 14.) PharmaLinx LLC, publisher of the VIEW, welcomes comments about this article. E-mail us at [email protected].

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