6 June 20 08 VIEW on Clinical Operations THE FORUM A recentTufts CSDD study cites research showing that the cost to develop a new biopharmaceutical is now more than $1 billion. Accordingly, clinical organizations are under growing pressure to reduce research and development costs while accelerating development timelines. Clinical operations execu tives in particular are being called upon to manage drug devel opment functions more efficiently and effectively and to save money while doing so. They are rising to the challenge by improving their collaborations with CROs and investigative sites and employing technologies to streamline and optimize the collection and dissemination of clinical data, making it easi er for R&D executives to quickly decide which candidates war rant continued investment and which need to be left behind. TECHNOLOGY BENEFITS According to Tufts CSDD, the nearterm ability of drug developers to survive and thrive in the current environment will flow largely from their ability to evolve their management and information systems to improve access to new develop ment platforms and tools. Clinical operations leaders have adopted a number of best practices and cuttingedge tools to manage the overall complexities and costs associated with clin ical trials. Among the most widespread technologies are electronic data capture (EDC) systems, which according to Ren Belder, M.D., senior VP, clinical and regulatory affairs at Pharmacopeia, have significantly improved companies’ ability to manage clini caltrial programs. “Remote data entry has affected the way trials are con ducted by providing access to data the moment the informa tion reaches computers,” Dr. Belder says.“It makes it easier for physicians to monitor the study and allows for earlier detec tion of potential safety signals.” Another tool being employed by the industry is the clini cal trial management system (CTMS). “Having an effective clinical trial management system is key to facilitating the planning and tracking of study deliver ables within the desired time and cost constraints,” says Maria Smith, global head, clinical operations affiliates, at Roche.“EDC is also critical to facilitate the collection and review of clinical study data in a timely manner.To drive compliance and quali ty, we launched a quality risk management project that com bines FMEA (failure modes and effects analysis) principles with data mining of quality relevant data elements and as such, this allows us to monitor in real time the performance and compliance of all entities involved in a clinical trial — sites, CROs, internal processes, and so on.” While many companies are banking on technologies to improve their clinicaltrial processes, they may not be getting the most out of their systems because of some common mis takes that may occur during the implementation of compli cated and highly customizable systems, which can lead to delayed rollout or systems that simply “die” before they are enacted. To ensure the successful adoption of a CTMS, experts at Campbell Alliance say organizations should be aware of the most common errors associated with imple mentation. (For more information on the most common errors and methods to overcome implementation miscues, please turn to page 22.) According to recent study results cited by Wolfgang Renz, M.D., Ph.D., president of Samaritan Therapeutics, the by Carolyn Gretton Clinical Operations: Bringing All of the Pieces Together ccording to the Outlook 2008 report fromTufts Center for the Study of Drug Development (CSDD), the most successful drug developers in the coming years will be those who radically change their entire approach to business — from R&D to project management to manufacturing to marketing. AFTER DECADES OF RIDING WAVE AFTER WAVE OF INNOVATIVE NEW THERAPIES, pharmaceutical developers find themselves staring down a host of significant patent expirations, with the next generation of novel therapies not quite ready to make their market debut. A 0608 pvv layout FINAL 5/29/08 11:44 PM Page 6 number of pharmaceutical and biotechnology companies using EDC in clinical trials is projected to reach 48% this year, up sharply from 7% in 2005, constituting more than a fivefold increase in only a three year time span. Another 30% of pharmaceutical and biotechnology companies will employ EDC in 50% to 90% of their trials in the next year, Dr. Renz says. “Pharmaceutical companies are increasingly making EDC based trials a standard practice, and they are asking CROs to work with them in introducing technologies that will add effi ciencies and greater standards of quality to clinical trials,” Dr. Renz adds. Greater regulatory emphasis on proving safety and effica cy has led to growing standardization and automation of all aspects of clinical trials. Dr. Belder says this standardization has made it easier for regulatory agencies, such as the U.S. Food and Drug Administration, to more quickly accept and orga nize clinical data. “Standardization ultimately will probably make it easier for companies that inlicense compounds for which there is already a database available to quickly take the product over THOUGHT LEADERS # REN BELDER, M.D. Senior VP, Clinical and Regulatory Affairs, Pharmacopeia Inc., Cranbury,N.J.; Pharmacopeia is a developmentstage biopharmaceutical company dedicated to discovering and developing novel smallmolecule therapeutics to address significant medical needs.For more information, visit pharmacopeia.com. # KAMRAN HOSSEINI, M.D., PH.D. VP, Clinical Affairs and Chief Medical Officer, InSite Vision Inc., Alameda,Calif.; InSite Vision is an ophthalmic company focused on therapies that treat ocular infections, glaucoma,and ocular diseases. For more information, visit insitevision.com. # MARK J. PYKETT,V.M.D., PH.D., MBA. President and Chief Operating Officer, Alseres Pharmaceuticals Inc., Hopkinton,Mass.; Alseres Pharmaceuticals is a biotechnology company engaged in the development of biopharmaceutical products for the treatment of traumatic injuries and degenerative diseases. For more information, visit alseres.com. # WOLFGANG RENZ, M.D., PH.D. President, Samaritan Therapeutics, Montreal; Samaritan Therapeutics is a Canadiancontrolled private biotechnology company focused on developing innovative drugs to treat Alzheimer’s disease, cancer, heart disease, and infectious diseases; Samaritan Therapeutics is minorityowned by Las Vegasbased Samaritan Pharmaceuticals Inc. For more information, visit samaritanpharma.com. # STEPHEN M. SIMES. President and CEO,BioSante Pharmaceuticals Inc., Lincolnshire, Ill.; BioSante Pharmaceuticals is a specialty pharmaceutical company focused on developing innovative testosterone and estrogen products for female sexual health, menopause, contraception,and male hypogonadism.For more information, visit biosantepharma.com. # MARIA SMITH. Global Head,Clinical Operations Affiliates, Roche, Nutley, N.J.; Roche is one of the world’s leading researchfocused healthcare groups in the fields of pharmaceuticals and diagnostics.For more information, visit rocheusa.com. # SUSIETRUONG. Director of Finance and Administration, Cequent Pharmaceuticals,Cambridge,Mass.; Cequent Pharmaceuticals is an earlystage biopharmaceutical company that is pioneering the development of novel therapeutics to prevent and treat a wide range of human diseases — from inflammatory diseases to cancer.For more information, visit cequentpharma.com. # BEATWIDLER, PH.D. Global Head,Quality Assurance,Roche, Basel, Switzerland; Roche is one of the world’s leading researchfocused healthcare groups in the fields of pharmaceuticals and diagnostics.For more information, visit rocheusa.com. Maria Smith Roche 7 VIEW on Clinical Operations June 20 08 THE FORUM and continue development with no lag time from the time it took to complete the acquisition,” Dr. Belder adds. According to a PhRMAsponsored Gartner study, more than half of the value of implementing standardized data and processes occurs during the study startup stage, which can reduce time for these activities by 70% to 90%. Medidata Solutions experts believe that in recognition of these bene fits, many pharmaceutical companies are looking for tools to enable structured data creation at the studydesign stage, which has led to the emergence of the eprotocol.The basic premise behind the eprotocol is that the immense amount of work already performed at the study design and proto col development phases can be leveraged throughout the clinical process, rather than being manually copied and rein terpreted throughout the process. (To learn more about the eprotocol process, please turn to page 24.) Pharma was initially slow to adopt electronic tools for clinicaltrial management, in part because of the heavily regu lated nature of the industry, Dr. Belder says. “Pharma’s hurdles to incorporate newer technologies are more difficult because of the large amount of validation Having an effective clinicaltrial management system is key to facilitate the planning and tracking of study deliverables within the desired time and cost constraints. EDC is also critical to facilitate the collection and review of clinical study data in a timely manner. 0608 pvv layout FINAL 5/29/08 11:44 PM Page 7 Dr. Kamran Hosseini InSite Vision 8 June 20 08 VIEW on Clinical Operations THE FORUM that needs to occur,” he says. “To a certain extent, the airline industry is undergoing the same challenges; flight control centers are still working with equipment that’s decades old. There are a lot of good, newer technologies available, but they haven’t been validated; this is a huge undertaking. “But the pharmaceutical industry is getting there, and that’s good,” Dr. Belder continues. “When I first came to the United States, BristolMyers Squibb had filed a paperbased NDA for pravastatin, and it took a whole truck to get all the paper to the FDA, not to mention the amount of time it took regulators to sift through all the data. Now the process is much more rapid; if a company has a team prepared to put everything together the minute its last study is complete, the NDA can be filed very quickly.That wouldn’t have been pos sible a decade ago. So there definitely have been enormous productivity gains in this regard.” Thought leaders at PHT Corp. agree that one of the key benefits of esource technologies is the ability to shorten the time to database lock and data analysis.Technologies such as ePRO eliminate many of the bottlenecks associated with collecting questionnaire data on paper, such as double data entry, queries, and other costly delays. Additionally, industry research indicates that 50% to 60% of trials capture health related quality of life (HRQL) and other questionnaire data. This figure is expected to rise significantly, considering the FDA’s PRO Draft Guidance and its emphasis on involving the patient perspective. (To learn more about how ePRO can be used to improve the trial process, please turn to page 26.) Standardized technical, legal, and financial strategies are also crucial to good clinicaltrial management practices, says Kamran Hosseini, M.D., Ph.D.,VP, clinical affairs and chief med ical officer, at InSite Vision. “Optimizing mission success is dependent on timely recognition and classification of risks related to technical, legal, and financial domains,” Dr. Hosseini explains. “Acceler ating the clinical development critical path can be achieved by developing appropriate contracts and expediting subject Accelerating the clinical development critical path can be achieved by developing appropriate contracts and expediting subject enrollment strategies, which may also contribute to healthy budget control. And employing strategies to oversee misconduct and fraud is a must to protect patient safety and prevent possible legal and regulatory consequences. A Typical _______ [adjective] Article About the FDA By Peter Pitts [BIG CITY], [date] — Today [adjective] Citizens for [superla tive adjective] Health released a [adjective] metaanalysis that [adverb] concludes the FDA “is in the [noun] of [adjective] Pharma.” “Our research of [number] concerned [plural noun] points [adverb] to an agency that has once again [verb past tense] the American public. It’s a [adjective] indication that the FDA places [noun] over [noun] and cannot be trusted to [verb] or [verb] — and certainly not [verb] in the public interest,” said the author’s report Dr. Egor [type of animal]. The study showed that most new drugs for a wide variety of chronic [type of disease] are ineffective and also [adjective]. In the case of [brandname drug] it was shown that [plural noun] were more likely to [verb] from [human organ] attacks than patients on older and [adjective] medicines. “I find this new report both [adjective] and [adjective] — but [adverb] not [adjective],” commented Congressman Bartholomew [type of insect]man. “And intend to hold tele vised [plural noun] on the matter.” “This is just another [adjective] example of the FDA’s lack of [adjective] [noun],” added Dr. [name of automobile compa ny] Buttersworth. If I were the FDA Commissioner this [adjec tive] circumstance would never have occurred.” In an embargoed editorial in the New [name of country] Journal of Medicine, Dr. Ethel [type of cake] opined that the [adjective] problem “is caused by the Prescription [noun] User Fee Act and made even [adjective] by the agency’s continued [verb] of directto[noun] advertising.”The editorial also points to the need for [adjective] importation of prescription [plural noun] from [name of country]. Supporting this notion, the [any acronym] added that in addition to being [adjective], high [plural noun] for brand drugs are a result of the [type of shrub] Administration’s [adjective] program known as Part [letter] and called for [name of movie studio] care. The FDA had [adjective] comment. Peter Pitts President, Center for Medicine in the Public Interest and Former Associate Commissioner, FDA EDITOR’S NOTE: PETER J. PITTS, A FORMER FDA ASSOCIATE COMMISSIONER AND PRESIDENT OF THE CENTER FOR MEDICINE IN THE PUBLIC INTEREST, POKES SOME FUN AT THE ARTICLES BASHING THE FDA BY TAKING A PAGE OUT OF THE CLASSIC “MAD LIBS” PUBLICATION. MR. PITTS CAN BE REACHED WITH COMMENTS AT [email protected]. 0608 pvv layout FINAL 5/29/08 11:44 PM Page 8 With solutions for Trial, Site and Patient Intelligence, etrials will work to understand your study goals, then propose an adaptive solution that delivers endtoend visibility in virtual realtime for greater study control and management, resulting in perfectly informed decisionmaking and better trial outcomes. Learn more at www.synchronizedintelligence.com. 10 June 20 08 VIEW on Clinical Operations THE FORUM enrollment strategies, which may also contribute to healthy budget control. And employing strategies to oversee mis conduct and fraud is a must for companies to protect patient safety and prevent possible legal and regulatory con sequences.” While many developers outsource some or all of their clinicaltrial management processes, some believe it’s best to manage those functions inhouse. “Obviously computers are key, with the appropriate soft ware to track all aspects of recruitment, randomization, and data collections, but our people are still the critical technolo gy,” says Stephen Simes, president and CEO of BioSante Phar maceuticals.“We believe our best practices in clinical trials are to control the process inhouse: we write the protocols, sub mit to the FDA, and negotiate directly with the FDA. And once the protocols are finalized we contract directly with investigators and monitor the trials, so we can thereby better control budgets and timeline.” In terms of protocol development, according to experts at Ateb, the genesis of each clinical project is preprotocol feasibility. By employing pharmacy outreach services, the study team can complete a thorough preprotocol analysis of the patient profile, indication prevalence, and population prevalence.This forerunner activity occurs before the pro tocol submission. (To learn how preprotocol development can help sustain study design at the inception to determine overarching success of the study, please turn to page 30.) CLINICAL FLEXIBILITY In other best practices, clinical developers are employing more adaptive clinicaltrial designs that take advantage of optimizing study sample sizes, according to Mark Pykett, V.M.D., Ph.D., MBA, president and chief operating officer of Alseres Pharmaceuticals. “There is increasing emphasis on the use of efficient clini caltrial designs and sophisticated statistical analysis plans,” Dr. Pykett says. “The advent of Bayesian statistics to drive adap tive trial designs facilitates the streamlining of subject sample sizes, earlier completion of studies, and the sparing of resources. Adaptive designs also allow for flexibility in dose ranges and less guesswork in picking appropriate protocol parameters, without sacrificing statistical rigor or power in support of demonstrating a drug’s effectiveness and safety.” According to Beat Widler, Ph.D., global head, quality assur ance at Roche, a better understanding of the disease biology, the rapid gain in knowledge of biomarkers and their applica tion to the clinical daytoday reality, plus the more wide spread introduction of novel statistical techniques, are chang ing the approach to early clinical investigation. “This approach will be critical in identifying deadends in clinical development early and to optimally position success ful new drug candidates,” Dr. Widler says. “If we want to be serious about personalized healthcare, then a onesizefitsall approach to clinical development can no longer be the path to follow.” “Adaptive clinical trials will undoubtedly have a place for certain indications and therapies,” Dr. Hosseini says. “They require different methodologies and a realtime multidisci plinary approach not yet fully and proficiently adapted by many pharmaceutical companies and their vendors. This expertise needs to be developed to effectively gauge the util ity of such an approach per indication, or else there is the potential that interim revisions to the study design could have a negative impact on the clinical trial.” In an effort to more quickly identify viable product candi dates, more companies are employing the exploratory IND (eIND) as an option for streamlining the earlyphase devel opment process. “In certain cases, exploratory INDs are wellsuited for entrylevel studies because they allow for firstinman evalua tions that are based on less nonclinical pharmacology, phar macokinetic, and toxicity data,” Dr. Pykett says. “This means that a significant amount of time and cost can be deferred until some key parameter of the agent has been demonstrat ed in the baseline eIND study. If the parameter is not verified through the eIND, resources that would have otherwise been expended can be spared. Of course, the tradeoff is that because lower doses and/or exposures are typically explored in an eIND, less information will be gathered than if a full IND had been pursued.” Dr. Widler hopes that the exploratory IND process will foster a dialogue between the FDA and sponsors and thus build the trust basis, allowing new models for development and techniques to be explored. “Any change in the regulatory framework that supports the introduction of novel approaches to development is wel come,” he says. Dr. Hosseini notes that the eIND is especially useful in effi ciently and rapidly identifying promising drug candidates in therapeutic categories such as cancer, where the ratio of failed drug candidates to successfully commercialized prod ucts is high. “The potential cost savings are enormous, and this will free up more funding for additional research,” he says.“Expos ing patients to very low doses of drugs will enable pharma ceutical company sponsors to collect valuable data for a meaningful trial while the safety of these patients is much less likely to be jeopardized.” When it comes to protecting the safety of patients in clin ical studies, there is a growing movement to develop guide lines for QT assessment in oncology agents, biologics, or large molecules.The agency is requiring data for these compounds with an eye on whether these trials will be needed in the future. Experts at Biomedical Systems are recommending that the sponsors include as many elements for the thorough QT (TQT) paradigm as possible as part of intensive QT tri als. (To learn more about the ICH E14, which gives guidance If we want to be serious about personalized healthcare, then a onesizefitsall approach to clinical development can no longer be the path to follow. Dr. Beat Widler Roche 0608 pvv layout FINAL 5/29/08 11:44 PM Page 10 11 VIEW on Clinical Operations June 20 08 regarding the conduct of socalled thorough QT trials, please turn to page 38.) THE PATIENT EQUATION Patient recruitment and retention are perennial problems for investigators and are major causes of delays in studies. Mr. Simes recommends using companies that specialize in study recruitment through news releases, advertising, and community outreach to attract patients that are wellsuited to the trial in question and thus may be less likely to drop out. “The right recruiter can effectively organize a campaign to realize timely recruitment,” Dr. Hosseini says. But, according to thought leaders at The Patient Recruit ing Agency, evaluating and allocating costefficient and cost effective advertising budgets for a patient recruiting campaign are issues that rarely receive the attention they deserve. (To learn why a wellplanned budget is absolutely integral to the success of any recruiting campaign, please turn to page 36.) “Retention is highly dependent on the patients’ relevant awareness and education and ultimately the sense of self responsibility that can be achieved through positive and respectful interaction with them,” Dr. Hosseini says. “Simplifying the protocol design can make it easier for patients, investigators, study monitors, and contractors to fulfill all of their obligations toward maximum retention of patients in the database,” Dr. Pykett adds. “Also, limiting the duration of follow up and the number of followup visits, if at all possible, can lessen the timedependent attrition of patients in a study.” Ms. Smith says companies need to consider the patient’s perspective when designing clinical trials. “It’s important that we clearly convey what the benefits and risks of the trial are, what the experimental treatments are, and the rationale for the frequency of visits and assess ments that will be performed, and that we partner with sites to provide information that is of benefit to patients,” she says. Dr. Renz notes that it’s essential to identify the best geo graphical regions and sites with proven recruitment records and protocol compliance. Consulting key opinion leaders in all regions involved substantially helps in pinpointing the best routes to take when introducing a new clinical trial for a spe cific therapeutic indication. Experts at Inclinix agree that it’s vitally important to ques tion whether the needed patients are available at the inves tigator sites. Answering this question incorrectly means that the clinical trial will fall short of its goal, and most trials run late due to patient enrollment issues. (Please turn to page 34 to read a case study that illustrates how early scrutiny allowed the use of directtopatient advertising to solve an enrollment shor tfall, before it occurred.) CROS AND OUTSOURCING According to Tufts CSDD, more difficult protocols and lower compensation could inhibit study efficiency.The burden on investigative site personnel to execute study protocols increased 10.5% annually between 2000 and 2005, as the number and frequency of procedures per protocol increased. During this same period, site compensation per procedure declined by almost 2% in nominal dollars. Drug sponsors are expected to employ new site selection and management practices and electronic clinicaltrial technol ogy solutions to improve study conduct inefficiencies. While global clinical grant spending continues to rise — exceeding $8 billion in 2007, according toTufts CSDD — half of all sites con tinue to underperform or fail to enroll patients into trials. Therefore, sponsors are likely to focus more attention on sim plifying and streamlining protocols to reduce conduct delays and improve investigative site adherence and performance. To that end, demand for contract research organization (CRO) services is projected to increase by 16% annually over the next three years as sponsors seek assistance in managing large, complex global projects without increasing their inter nal headcount, the Tufts CSDD study says. Dr. Pykett notes that specialized contract research organi zations can provide key expertise the company doesn’t have internally, and deliver services on a variable cost basis that can limit carrying costs. “A combination of contractors can often provide knowl edge depth and efficiency the organization could not other wise achieve,” he says. Roche’s Ms. Smith agrees that the optimal approach is to have several preferred partners to optimize the working rela tionship. “And, if needed, we consider a niche CRO when a specif ic expertise is required,” she adds. Some characteristics clinical operations executives cite as crucial for a good CRO partner include therapeutic exper tise, good working chemistry, efficiency in operations, and consistent, personalized attention. “Pharmaceutical companies expect a true partnership and want to work with a CRO that has a sense of ownership and accountability for their programs,” Dr. Renz says. “CROs must play a proactive role to identify the problems and to offer adequate solutions. CROs help to improve healthcare Dr. Mark Pykett Alseres Pharmaceuticals There is increasing emphasis on the use of efficient clinicaltrial designs and sophisticated statistical analysis plans. The advent of Bayesian statistics to drive adaptive trial designs facilitates the streamlining of subject sample sizes, earlier completion of studies, and the sparing of resources. 0608 pvv layout FINAL 5/29/08 11:44 PM Page 11 12 June 20 08 VIEW on Clinical Operations THE FORUM worldwide by providing a broad range of professional services, information, and partnering solutions to the pharmaceutical, biotechnology, and healthcare industries.The CRO does what the sponsor needs and the way the sponsor expects at an optimal cost.” “There is no substitute for a track record in the specific area of expertise for which the CRO is being hired,” Dr. Pykett says. “Even if cost differences support a lesspracticed partner, our experience would suggest that the price for getting a part ner along the learning curve can consume their economic advantage, and the risk of failure remains higher during the process.” Dr. Belder says Pharmacopeia, which has a cardiovascular drug candidate in Phase II trials, selected one of its CRO part ners based on its technical expertise in conducting ambula tory bloodpressure measurements. “The CRO had a lot of experience with these types of measurements, and the investigators associated with the CRO were wellknown in the field,” he says. Developers often must decide whether to go with a sin gle CRO or to select multiple CRO partners based on their various areas of expertise. “Given the expertise often required in multiple, dis parate areas of drug development, we find it preferable to Remote data entry has affected the way trials are conducted by providing access to data the moment the information hits the computers; this makes it easier for physicians to monitor the study and allows for earlier detection of potential safety signals. What’s in Your Supply Closet? Many smaller startup companies in the biotechnology sector face the chal lenge of managing supplies and consumables amid deadlines and milestones. In addition to the limited manpower that is devoted to purchasing and receiving, biotech startups must manage costs right out of the gate. It is important for companies of all sizes to have accurate recordkeeping, appropriate cost controls, and policies in place for purchasing goods and services used in R&D. The problem, of course, is that at some point the pursuit of scientific research and management chores collide. If the company doesn’t take steps to ensure operational efficiency, it will waste time and money on nonessentials that do nothing to advance the critical research it is conducting. The company may burn through funds and having nothing — or at least not enough — to show for it. At Cequent Pharmaceuticals, progress is measured by several benchmarks. In addition to meeting our goals, we must also ask: does the company maximize its efficiencies and can we do more to streamline spending when revenue is not yet on the horizon? Cequent orders numerous items used in drug discovery from more than 150 different suppliers, and we had traditionally managed all those orders through a timeconsuming, paperbased system consisting of handwritten Postit notes, emails, and scraps of paper. After two months of increasing purchasing activity and spending, we wanted to evaluate our purchasing policy to take advantage of cost savings wherever possible. Time is a currency that is often more valuable than money for biotech busi nesses. Even if generously backed by venture capital, companies must show investors that milestones are being met and progress is being made.There is a delicate balance between managing costs and accelerating progress.When saw we were falling behind on inventory management, knew we needed to take a more sophisticated approach to procuring supplies to keep our entire business on track. But there was a catch.When we researched eprocurement solutions, some vendors told us we were too small for them to even consider our business. Additionally, most commonly used enterprise software applications seemed to add more complexity to our business processes rather than simplifying them.The majority of eprocurement implementations fail or are abandoned because employees find it easier not to use them, despite the time and expense involved in implementation and training. At Cequent, most workers were so engaged in their research they had little interest in learning a new software program related to ordering supplies. Ultimately we discovered another approach, an eprocurement software delivered under a SaaS (software as a service) model. SaaS is hosted as a service across the Internet, eliminating the need for com panies to install software or provide ongoing maintenance.The SaaS model also eliminates a lot of the upfront investment and time requirements associated with buying and installing enterprise software, while also providing employees with more ongoing suppor t. The eprocurement software is designed to simplify purchasing for small and mediumsized businesses and we were able to get the software up and running swiftly so that we could better monitor orders and spending. And since SaaS solu tions incorporate userfriendly Web 2.0 capabilities, we had little trouble getting employees to adopt it. It quickly became apparent how this software simplified their lives — and mine. With a new eprocurement solution, Cequent moved quickly from not know ing what was in the supply closet to being able to track which items employees were ordering, the prices they were paying, and the dates the shipments were received. Within three short months, the software had paid for itself. We were able to track trends in ordering and bundle orders to save on shipping expenses and han dling fees. The SaaS provider we engaged was able to use the data to negotiate more favorable pricing with our top 10 vendors. Additionally, we gained the abili ty to approve purchases via our email system to create an audit trail that appeased our auditors. As a result, Cequent effectively eliminated one key distraction in the way of our core mission of finding new ways to treat many diseases that are far more serious than the headaches that come from ordering a box of gloves when a whole case is required. SUSIE TRUONG, DIRECTOR OF FINANCE AND ADMINISTRATION AT CEQUENT PHARMACEUTICALS, TALKS ABOUT HOW SHE MOVED CEQUENT TO A SAAS PROCUREMENT MODEL TO HELP THE BIOPHARMACEUTICAL COMPANY FOCUS ON MORE IMPORTANT TASKS. Dr. Ren Belder Pharmacopeia 0608 pvv layout FINAL 5/30/08 1:18 PM Page 12 14 June 20 08 VIEW on Clinical Operations THE FORUM use multiple CROs to access the specific organizational knowledge capital required for the best outcome,” says Dr. Pykett, whose company, Alseres, is researching a number of drug candidates across a broad spectrum of traumatic injuries and neurodegenerative conditions. “Using a series of CROs can also mitigate certain risks associated with a single contractor and can in some cases lower expenditures as we access different cost structures,” he continues. “However, simultaneously this approach can increase the internal requirements to actively manage the CROs and may lead to additional complexity if the project requires CRO integration.” “Certain CROs have developed expertise and experience for a group of indications over the years,” Dr. Hosseini says. “Obviously, working with these CROs for a certain indication can significantly increase the likelihood of seamless interac tions. But we need to consider the overall proficiency of a CRO to select a final partner.” Roche has established partnerships with a select number of CROs to facilitate a working relationship. “Some expected outcomes include enhanced efficiency, flexibility, and decreased development time as we work seam lessly with the same companies and their people over time,” Ms. Smith says. Other developers believe companies, especially smaller organizations, should find one CRO that meets all their devel opment needs. “Pharmaceutical companies should seek a single fullser vice CRO partner that can handle a full drugdevelopment program,” Dr. Renz says. “That way, fewer inhouse employ ees are needed, while efficiently coordinating, managing, and supervising various project activities within expected time lines and especially, within budget.” Thought leaders at inVentiv Clinical Solutions contend that biopharmaceutical companies should explore alterna tives to the traditional paradigm of fullservice clinical trial outsourcing to maintain appropriate levels of control that lower their overall drug development costs. As such, there is a growing trend toward flexible, integrated outsourcing models that allow the proper blend of tactics for current development needs that can be adapted quickly to meet the changing needs of the organization and the industry. (To learn more about flexible and adaptable outsourcing mod els, please turn to page 32.) GROWING GLOBALIZATION Pharmaceutical companies are conducting more and more clinical trials in countries other than the United States. For example, China and India have become increasingly attractive to drug developers because of reduced expenses and easy access to large populations of previously untreated patients available for clinical studies. According to the Tufts study, with in the next three years, up to 65% of FDAregulated clinical tri als for the top pharmaceutical companies will be conducted outside the United States, up from 43% at present. Most clinical operations executives agree that the trend toward globalization will continue. Dr. Wolfgang Renz SamaritanTherapeutics Pharma companies are increasingly making EDCbased trials a standard practice, and they are asking CROs to work with them to introduce technologies that will add efficiencies to the clinical trials. 1400 1200 1000 800 600 400 200 0 Millions (2005$) Outofpocket cost Time cost Total cost 12% 10% 8% 6% 4% 2% 0% Growth Rate 20002005 Investigative Site Protocol Design Changes Number of Unique Procedures Frequency of Procedures Execution Burden Compensation per Procedure The burden on investigative site personnel to execute study protocols increased 10.5% annually between 2000 and 2005 as the number and frequency of procedures per protocol increased. During this same period, site compensation per procedure declined by nearly 2% in nominal dollars. Source:Tufts Center for the Study of Drug Development Outlook 2008. For more information, visit csdd.tufts.edu. Preclinical Clinical Total *Total biopharmaceutical R&D costs include the cost of molecules that fail in testing and the time cost of investing in development years before any potential returns can be earned.Time costs account for more than half of the total cost per approved new biopharmaceutical of $1.2 billion for recombinant proteins and monoclonal antibodies that entered the clinical testing pipeline from 1990 to 2003. Source: Joseph A. DiMasi and Henry G. Grabowski, Managerial and Decision Economics,Vol. 28, issue 45, pgs. 469479 (2007). Reprinted in Tufts Center for the Study of Drug Development Outlook 2008. For more information, visit csdd.tufts.edu. Preapproval R&D Costs Per Approved New Biopharmaceutical* 0608 pvv layout FINAL 5/30/08 1:18 PM Page 14 15 VIEW on Clinical Operations June 20 08 THE FORUM “If companies want to run programs efficiently and to enroll patients quickly, they need to be conducting global development programs,” Dr. Belder says. “This global trend is not going to diminish.” Dr. Pykett says in the drugdevelopment world globaliza tion is a necessity, given the global scale on which drug com mercialization is ultimately sought. But globalized trials carry risks as well as benefits. Negoti ations with local agencies and companies can prove costly and timeconsuming, requiring companies to seek clinical and regulatory perspectives that take into account the intricacies of the region. “Sponsors need to better understand and overcome chal lenges such as the language barrier and cultural diversities to anticipate patient enrollment and compliance throughout the studies,” Dr. Hosseini says. “Additional and evolving regulatory and safety aspects for certain types of studies in some parts of the globe also call for extra vigilance.” According to experts at MediciGlobal, there’s a new twist on globalization, called “glocalisation,” which is a combination of thinking globally and acting locally. And this is changing how patient recruitment and retention literature needs to be developed. (To learn how technology is improving glob al processes, please turn to page 28.) Ms. Smith believes that the competition for clinicaltrial sites continues to increase but the number of new investi gators is not keeping pace. “Investigators in emerging economies are eager to pro vide their patients with opportunities for enhanced medical care,” she says. “Labor and travel efficiencies are also important to drug development and commercialization in other countries,” Dr. Pykett adds. “And territoryspecific approaches to sales and marketing are important to successful regional commercial ization.” LEADING THE TEAM Because of the complexity and continually changing nature of clinicalstudy management, communication and planning skills were two of the attributes most frequently cited as critical to becoming a strong leader in the clinical operations setting. “Good planning is the key for any great operations exec utive,” Dr. Renz says. “Also, clinical operations teams should work to develop strategic action plans focusing on high value/highreturn activities, create metrics for key clinical activ ities, implement efficient study management procedures, and ensure clear communications between team members to clarify deliverables and accountabilities, while meeting estab lished timelines and the expected standards of quality.” At Roche, clinical operations staffs are located throughout the world. As such, the company has developed RACI (responsible, accountable, consulted, informed) charts that clearly define who is accountable and responsible for certain activities to avoid duplication of effort and ensure a more effective allocation of resources. When it comes to finding great clinical operations execu tives, Ms. Smith says Roche looks for people who have had reallife experiences in various roles. Stephen Simes BioSante Pharmaceuticals 80% 70% 60% 50% 40% 30% 20% 10% 0%a Small/MidTier Approvals Large Pharma Approvals Share of Approvals Note: * Includes government, academic centers, nongovernment organizations, nonprofit groups, and hospitals. Source:Tufts Center for the Study of Drug Development Outlook 2008. For more information, visit csdd.tufts.edu. Large Pharma Origin Small/MidTier Origin Other * Notes: Dollars are based on 2005 rates and are in Millions; * All R&D costs (basic research and preclinical development) before initiation of clinical testing; ** Based on a fiveyear shift and prior growth rates for the preclinical and clinical periods. Source: Joseph A. DiMasi and Henry G. Grabowski, Managerial and Decision Economics, Vol. 28, issue 45, pgs. 469479 (2007). The Cost of Biopharmaceutical R&D — Preapproval Capitalized Cost Per Approved New Molecule Patient recruitment and retention are perennial problems for clinical investigators and are major causes of delays in clinical trials. Biotech Pharma Pharma (timeadjusted)** Preclinical* Clinical Total 615 376 439 626 523 879 1,241 899 1,318 Origin of New U.S. Drug Approvals (20002006) 0608 pvv layout FINAL 5/30/08 1:18 PM Page 15 16 June 20 08 VIEW on Clinical Operations THE FORUM “For example, former monitors are more sensitive to the issues and challenges this role faces,” she says. “We also rec ognize that there needs to be a balance between standard ization and the need to be flexible to meet the demands of clinical research across the different disease areas and phas es of development.” Executives also need to have extensive clinical knowledge and experience to succeed, Dr. Pykett says. “Leaders have to have an eye toward the big picture, the ability to see through to the key efficacy outcome measures, and how the study will support the ideal drug label and target product profile; skill at wringing out clinical development risk; an ability to identify trial designs that minimize cost and time without raising risk or sacrificing the drug’s market potential; and indepth knowledge of the clinical landscape in an effort to align the drug with optimal indication positioning,” he adds. “At the end of the day, it’s all about successful translation of biological knowledge into medical practice through clinical trials,” Dr. Hosseini agrees. “A great clinical operations execu tive stays abreast of the modern discovery findings and pre clinical models, bridging the lab science with the clinical and regulatory domain. I’d compare a good clinical executive to a great music conductor who in this case helps groups of mul tidisciplinary scientists to interpret and perform pieces of drug development.” Still, Dr. Belder asserts that a top clinical executive must excel at team leadership above all. “It goes without saying that the person needs to have a good understanding of what drug development is and which pieces need to be taken care of in a drugdevelopment pro gram,” he says. “In a large organization, this person has to be able to hire the right people for the various tasks. He or she has to be able to communicate the vision and then be able to manage the team members effectively so that they can exe Insights From the Insiders PHARMAVOICE ASKED EXPERTS IN THE CLINICAL ARENA TO IDENTIFY THE CURRENT BEST PRACTICES BEING EMPLOYED TO MANAGE THE OVERALL COMPLEXITIES AND COSTS ASSOCIATED WITH CLINICAL TRIALS. Kathleen Drennan Managing Director Iris Global Clinical Trial Solutions For more information, please turn to page 20. Execution Before Trial Initiation From our perspective, best practices occur when a very clearly executed strat egy and tactical plan is developed before the study has even begun and when relevant market research and feasibility studies are incorporated. Unfortunately, this is a rare occurrence. In this industry, very few study sponsors implement best practices for man aging overall complexities and costs. Each study sponsor has a different approach or set of guidelines to budgeting, contract negotiations, invoicing, and cost man agement. Unfortunately, there are companies that will only pay for what they perceive as essential to the trial. But these approaches to budgeting do not often coin cide with what is truly needed or essential to move the trial forward and com plete it on time. Additionally, multiple suppliers are often used for a single trial, which compli cates things even more. Managing the complex relationships and communica tions can cause redundancies, increased inefficiencies, and increased costs. Clear ly with more than 80% of trials either being delayed or moving into rescue mode, the complexities (i.e., patient recruitment, site selection, and performance) are not being managed well with best practices. Bill Gwinn VP, New Product Development Inclinix Inc. For more information, ple se turn to page 34. Planning and Preparation From my perspective at a contract research organization, best practices begin with use of research and metrics for strategic planning and prepara tion. Much of the traditional planning in the industry is about logistics after patients enroll in the trial. Because getting patients enrolled is the most like ly source of delay, planning must begin before patient recruitment and site selection. Finding the best sites includes ranking areas according to disease preva lence. You can “fish where the fish are” to find patients. These same research databases are the foundation of advertising tools and techniques for outreach campaigns.There is statistical modeling to predict enrollment. After the trial begins, best practices start with centralized site management tools to understand site status.The foundation of good cost control is being able to predict the obstacles. Nobody can do that flying blind. At minimum, there are online tools for tracking patient status in real time. For a more comprehensive pic ture, best practices are evolving toward clinical trial management systems inte grated with electronic data capture of patient information. The creators of the best systems have mined historical data to create norms for comparison with each trial’s interim results. S. Yin Ho, M.D., MBA VP, Product Strategy Medidata Solutions Worldwide For more information, please turn to page 24. Think Optimal Practices, Not Necessarily “Best” Practices “Best practices” are usually defined as current processes that work effectively to solve a particular problem. But what happens when best practices fall short of optimal practices? For example, management of clinical trials has been suboptimal, even if effective, when sponsors fail to recognize that protocol design complexity affects trial execution risk and resulting costs. Too often trials are designed with ideal patients and measurements in mind, or are a consolidation of multiple trials measuring similar, but subtly different effects. In either case, the need to “reality test” the protocol and its effects on sites and patients is the key to driving down execution risk. Three practices that can be applied more consistently are: 1) testing the pro tocol design among practicing community physicians, rather than only academic thought leaders or physicians away from patient care for more than a few years; 2) confirming that the disease epidemiology matches the recruitment plan ratio nale (e.g., the face of HIV in the United States is increasingly that of AfricanAmer ican heterosexual women in more rural communities, thus sites should be select ed from where they live); and 3) making sure sponsor processes are predictable and reliable enough to fully support the sites (e.g. ensuring drug shipments will be ready at the time of investigator meetings). Pressuretesting protocols and execution plans against realworld logistical realities is a best practice that will enable firms to anticipate and address down stream execution risks and subsequent costs, which will in turn generate optimal results. 0608 pvv layout FINAL 5/30/08 1:18 PM Page 16 17 VIEW on Clinical Operations June 20 08 THE FORUM cute. A good operations executive hires the people who see more efficient ways of doing things, who will continuously look for even better methods, and who are adaptive to solving problems and issues through the development process.” MOVING FORWARD In the near term, most experts agree that the clinical development process will continue to evolve, albeit at a more measured pace than in the past few years. Thought leaders at Iris Global Clinical Trial Solutions say there has never been a better time for change in the way the industry approaches the completion of clinical trials: it’s time to go beyond the protocol and embrace a newer way of thinking and planning for a trial. They believe the answer lies in adopting an intelligent trial approach, which takes into account the requirements of the study sponsor in validating its science; the needs of the physician in providing options to patients; and the desire of patients for better treatments or cures, whereby the whole system of values are analyzed rather than simply its individual components. (For more information about intelligent trials, please turn to page 20.) “Clinical trials will undeniably be more complicated as medical science combats more complicated diseases,” Dr. Renz says.“Technology will play a more complex and strate gic role in facilitating the execution and management of these large, complex studies. We must also take into account that there are new geographic regions involved in clinical trials, such as Latin America, India, and China.” The existing consolidation trend among pharmaceutical companies will likely filter down to clinical services vendors, Dr. Renz adds. “In five years, I believe there will be fewer vendors, and most likely those vendors will offer a full range of services, from project management to data management, monitoring, and writing reports,” he says. Dr. Pykett predicts a continuing focus on innovation and platform development from smaller organizations, as well as deals between large pharma and smaller drug developers to fill pipelines. “There will be continuing emphasis on developing effec tive drugs that do not meet traditional blockbuster parame ters, as pharma builds out increasingly specialized franchises in smaller market segments,” he adds. “The productivity with respect to coming up with new molecules has probably lagged a little bit in recent years,” Dr. Belder says. “All the lowhanging fruit have been plucked, and targets have become harder to identify. We understand a lot more about biology and molecular mechanisms, but the knowledge base on how to interfere with these systems hasn’t caught up. It’s getting there, but it takes awhile before truly novel therapies come out of that process. The whole genetic revolution of the past decade still has to result in novel therapies, and this is taking longer than people had hoped.” PHARMALINX LLC, publisher of the VIEW, welcomes comments about this article. Email us at [email protected]. Insights From the Insiders Katherine Luca Nicholson Client Advocate Biomedical Systems For more information, please turn to page 38. RealTime Access is Mission Critical From a core diagnostic lab perspective, giving pharmaceutical sponsors the abil ity to view their data in real time has become a critical component in modern clinical operations. By using secure Webbased access to a database portal, spon sors can get an immediate overview of the number of diagnostic tests per formed, PDFs of the tracings, alert notifications, queries, and other pieces of essential information, which enable them to make more informed decisions on how the trial is being managed. Delays lead to higher costs and lost revenue. Improving the access to critical trial information can help sponsors manage their trials in a more efficient and costeffective manner. Elizabeth Moench President and CEO MediciGlobal For more information, please turn to page 28. Going Global Regulators are demanding more patients, more data, more countries, and more complexity. As a result technologies aimed at cutting costs and time are essential, but technologies that allow for increased customization as well as those that bring another dimension. For patient recruitment and retention, technologies that speedi ly and costeffectively tailor materials to meet the needs of different ethnicities and cultures permit modern clinical trials to operate on a global basis — thinking global ly and acting locally. Furthermore,online systems that allow materials to be developed centrally, then locally adapted and approved online for content and translation in an instantly designed format, are delivering huge savings in time and costs, especially when materials are in IRBready format for review submission.These technologies are reducing the time delays and costs of intricate processes, while delivering truly glob al patient recruitment and retention materials. Sheila Rocchio VP, Marketing PHT Corp. For more information, please turn to page 26. Safety and Efficiency Eclinical technologies such as ePRO and EDC are helping sponsors manage clinical operations costs by making trials safer and more efficient. Protocols are getting more complicated; access to patients is extremely competitive, and sponsors are under pressure to deliver more therapies in a tougher regulatory environment. Eclinical technologies help researchers conduct better science with fewer resources. In par ticular, ePRO enables sponsors to capture reliable data directly from patients any where in the world and to monitor their safety throughout the course of the trial between visits. Realtime access to data allows investigators to manage compliance, enrollment, and safety while focusing less time on logistics and more time on caring for patients. PHARMAVOICE ALSO ASKED OUR THOUGHT LEADERS TO DISCUSS THE TECHNOLOGIES THEY THINK ARE MOST USEFUL IN HELPING TO MANAGE THE COSTS AND INTRICACIES OF MODERN CLINICAL OPERATIONS. 0608 pvv layout FINAL 5/30/08 1:18 PM Page 17
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