Outsourcing: Division of Labor

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DIVISION OF LABOR

There are about 7,500 projects under development by pharmaceutical and biotechnology companies worldwide, and an estimated 80,000 clinical trials are conducted globally every year. Today, 80% of these clinical trials are funded by private industry rather than by government, according to published reports. With so many potential drugs under review, there is huge pressure to be first to market. Therefore pharma ceutical companies look to improve every phase of drug development — from new approaches to discovery, to identifying therapeutic targets that optimize core com petencies, and finally to moving compounds more quickly into and through betterdesigned global clini cal trials. To ensure topquality trials, companies need to provide more staff training, adopt technology platforms, and under stand the critical importance of appropriate inclusion/exclusion criteria. The need to conduct faster trials has encouraged pharmaceutical companies to turn to outside con tractors, which are acting as partners to shorten the clinicaltrial process. There are now more than 10,000 research cen ters, ranging from academic settings to private prac tices, from managed care and physician practice management companies to integrated contract research service organizations. An estimated 50,000 principal investigators and 30,000 study coordina tors will conduct at least one clinical trial this year. Contract research organizations (CROs) play a significant role in almost twothirds of all clinical projects by providing monitoring, medical writ ing, and statistical services. There are about 850 CROs operating worldwide. Most of the large, publicly traded CROs, several generating more than $1 billion in revenue annually, have diversi fied into nontraditional services areas, including contract sales, marketing, and discovery research. In addition to helping drug companies speed the process of clinical trials, outside contractors offer an attractive global infrastructure, allowing sponsors to shift fixed costs, and providing a way for sponsors to manage peaks and valleys in the research pipeline. The trick is for sponsors and CROs to work together efficiently and cost effec tively, which entails building trust and processes that are compatible. Contract service organizations continue to reinvent themselves to suit the clients’ changing needs. CenterWatch reports 11% annual growth in clini cal spending, which has obvious implications for all phases of preclinical and clinicaltrial testing. Accord ing to UBS Securities LLC, about $3.14 billion was outsourced to CROs in 1997, an estimated $3.69 bil lion in 1998, $4.33 billion in 1999, and $5.09 billion by 2000, representing an average 17.4% annual growth in this fouryear period. To put that into per spective, companies spent an estimated $33 billion on R&D in 1997. Of that, $16.32 billion was spent on clinical development. According to the Association of Clinical Research Professionals (ACRP), a variety of outside contractors besides CROs stand to benefit WITH SO MANY POTENTIAL DR UGS UNDER RE VIE W,THERE IS HUGE PRESSURE TO BE FIRST TO MARKET. B Y L Y N D A S E A R S To SPEEDTHE CLINICALTRIAL PROCESS, pharmaceutical sponsors rely increasingly on outsourcing to MOVETHEIRPRODUCTSTHROUGHTHE PIPELINE Organizations must bewilling to accept a certain risk profile versus a reward opportunity byhaving information available earlier, and not all sponsors are prepared to do that.Some companies still revert to more conventional standards and processes of clinical development. CARY GARNER A optimizing drugdevelop ment cycle times. In some cases, making the clinicaltrial process more efficient relates to changing internal processes. The industry is responding in a variety of ways, albeit slowly, including developing technology to improve protocol design, clinical study startup activities, and patient enrollment all the way through to medical writing and NDA preparation. Adding Technology to the Equation According to ACRP, an international membership organization that represents more than 16,000 clinical research profession als from diverse organizations, despite tremen dous R&D expenditures the industry has been slow to invest in new technologies. Dozens of companies are beginning to spring up to address this void, specializing in providing software that increases the efficiency of the trial process — everything from discovery to patient enrollment to data capture to regula tory filing. Until recently, commercially available soft ware was not designed specifically for clinical trial simulation. According to ACRP, this is changing. Several companies have now devel oped software to simulate trials in all phases of development, enabling researchers to design, pretest, and study parameters. Among companies providing those soft from this positive trend, most notably academic medical centers, site man agement organizations, and individual sites and physi cian practice management organizations. “There is a lot of growth in outsourcing because that is an ideal way to optimize costs and procedures across a variety of fronts,” says Ken Getz, president and CEO of, CenterWatch. “In many cases outsourcing may be more cost effective, because a company can shift the cost to a vari able resource versus a fixed resource. By out sourcing, a company can often identify parties or partners that offer a certain level of expertise that it doesn’t have in house. And the assump tion is that an expert in a particular therapeu tic area or in a type of trial may be able to con duct the research faster. We also are seeing the use of trials technology as a way to address the challenge of optimizing efficiency.” Pharmaceutical companies are focused on OUTSOURCING for speed 31 PharmaVOICE M a r c h 2 0 02 INCREASING INTERACTION AMONG SECTORS. Perhaps the most interesting trend in the clinicaltrials industry is the increas ing interaction among sectors, which could lead to a blurring of dis tinctions between CROs, SMOs, AMCs, and independent sites. Although they clearly competewitheachother,they may actually add more value to the industry when they join forces to reduce trial time. In fact, this is already happening and seems to be the direction of the industry. COLLABORATIVEMODELS.There are a vari ety of collaborative models offering the sponsors increased efficiencies. For example, CROs often work with SMOs,an arrangement that could enable small companies to compete against large compa nies developing products in the same niche. As AMCs start to clean up their act to become more responsive to sponsors needs, their unique access to clinical thought leaders will make them attractive strategic partners. WORKING TOGETHER. CROs, SMOs, AMCs, and PPMs are all working together to further the industry’s mission of faster time to market. Independent sites fit into the equation because the good ones are coveted by SMOs seeking to expand their networks.The best way for a sponsor to be faster to market is threefold. First, use tools leading to rapid discovery,second, have excellently written protocols, and third, accumulate data that is reportable.The last two are strong opportunities for outsourcing organizations. TRACKING THE TRENDS: ACRP has identified the following trends: . Increased use of outsourced clinicaltrials services by sponsors seek ing to limit fixed costs,especially once they start packing pipelines with new chemical entities resulting from use of combinatorial chemistry, highthroughput screening,and genomics . Increased interest by sponsors in computerassisted trial design.CROs offering this capability may have a competitive advantage . Consolidation within sectors and among sectors to offer “fewerstop shopping” to sponsors seeking access to patientrich databases . Ongoing influx of venture capital,particularly into SMOs, further driving consolidation . Ongoing challenge of patient recruitment spurring interest in creative approaches . More physicians interested in becoming investigators, increasing the supply . Ongoing need for clinicaltrial services to embrace technology,which will position the industry to respond to the sponsor’s need for faster clinical trials; this includes equipping sites with appropriate stateof theart computerization and providing the requisite training . Training of people due to the growing complexity of trials — training is becoming more of a critical element, and should be done by CROs, sponsors, and clearly is a role for ACRP Source: Association of Clinical Research Professionals (ACRP),Washington,D.C. Blurring the Lines THE INDUSTRY’S SECTORS ARE WORKINGTOGETHER TO BRING DRUGSTO MARKET F ASTER When clinicaltrial newshits the headlines … it’s when things go wrong.Bad news is bigger news, in some respects.Patient enrollment is an enormous publicawareness problem — the biggest void is public awareness and education. DR.CINDY DUNN T OUTSOURCING for speed ware efficiencies are eResearch Technology Inc., which offers a suite of products and ser vices designed to streamline the conduct of clinical trials by enabling trial sponsors to migrate from manual, paperbased research methods to electronic forms of data collection, management, and analysis. Among the company’s products and ser vices is the eResearch Network, or eResNet, and Community Technology. “Through implementation of an eResNet, organizations can achieve scale economies in operations and processdriven integration to achieve industrybest practices,” says Scott Grisanti, senior VP of business development for eRT. “In addition the eResearch Communi ty delivers a command and control capability for access to applications and trialrelated infor mation.” Another company responding to the demand for clinicaltrial specific software is Phase Forward Inc., which offers eprocess solutions for accelerating global pharmaceuti cal development. Phase Forward’s InForm software product uses Internet technologies to conduct and manage clinical trials efficiently and effectively. Among its offerings are Clinsoft, a clinical database management and safety management system. “We believe that pharmaceutical com panies will continue to adopt our technologies because our endtoend clinical informatics solutions offer a substantial financial advan tage for both sponsors and investigative sites,” says John J. Schickling, Phase Forward’s chief financial officer. The Promise of Things to Come New tools such as combinatorial chemistry, highthroughput screening, and genomics hold the promise of helping researchers design a ver itable explosion of compounds that are effective, targeting the disease process rather than symp toms, with minimal side effects. Technology allows sponsors to dramatically increase the number of new chemical entities (NCEs) they discover and slate for development. Pharmaceu tical sponsors need many NCEs in their pipelines from which can come a stream of innovative products to feed investors’ demands for sustained doubledigit earnings growth. If the promise of technology results in the development of more NCEs, sponsors will need structured processes to send the successful NCEs through welldesigned trials to yield clean data. Contract service organizations, posi tioned to offer more sophisticated or niche ser vices, will play an expanded role. “It’s a challenge to integrate technology into the way we do business because some sponsors are not prepared, or their culture isn’t at the place that allows them to readily take advantage of technology,” says Mark A. Gold berg, M.D., president of Perceptive Informat ics Inc., a division of Parexel International Corp. “The pharmaceutical industry has invested relatively less in IT than most other industries. Even retail has invested, as a per centage of its revenue, considerably more than the pharmaceutical industry has. “To date, the pharmaceutical industry has 34 M a r c h 2 0 0 2 PharmaVOICE A s the marketplace for studyconduct sites becomes more competitive,academic medical centers (AMCs) may continue to lose market share unless they address a whole host of business issues.Those AMCs that perform competitively,and respond to sponsors’ needs in a timely and effective fashion will continue to grow,while the underperformers will be used less and less. Less than 10 years ago, the vast majority of industrysponsored clinicalresearch projects were conducted by faculty members in aca demic settings. Today, less than 45% of all projects are conducted there. An estimated 55% of the $4.5 billion spent on investigator grants are conducted by independent investigative sites, networks, and site management organizations. Academic medical centers have long received research grants from the pharmaceutical industry. But cutbacks in Medicare support for teaching hos pitals and the financial limits imposed by managed care have left many academic medical centers in a financial crisis. Additionally, in the 1990s the pharmaceutical industry started to shift a large portion of its research dollars away from academic medical centers to forprofit research companies that contract out with physi cians in private practice. In the face of this competition,many academic medical colleges have recently set up centralized clinicaltrial offices, modeled after those in the private sector, whose purpose is to streamline academ ic research, adjust to industry’s faster deadlines, and win back indus try grants. Academic centers are recognizing that they have other assets that can be used to offer contract projectmanagement services rather than studyconduct services. “The movement of academic medical centers forming alliances with CROs is a very interesting one,”says Ken Getz,president and CEO of CenterWatch Inc.“It doesn’t necessarily address being able to grow in the clinicalgrants market. A lot of these relationships are based on an academic institution’s ability to offer thoughtleader expertise, sta tistical analysis, and medical writing … a lot of the things that some of the traditional contract clinical service providers offer.” According to the Association of Clinical Research Professionals (ACRP), at a time when the goal of faster trials is driving the clinical outsourcing indus try, AMCs have a distinct role to play beyond pres tige. As hospital systems and networks consolidate, AMCsarebecoming theanchors for large integrated healthcare delivery networks.These include hospitals and clinics with access to big patient databases, often through managedcare con tracts. According to CenterWatch, the vision that is arising over and overamong the innovative academic medical centers is that of becom ing SMOs that facilitate research throughout their larger systems. AMCs seeking to overhaul their clinicaltrials business,according to ACRP, need to establish infrastructure, such as pairing an experienced study coordinator with a novice investigator, or linking promotions to increased volume of industrysponsored clinical trials. Several AMCs have programs to train new investigators. AMCS ARE BEC OMING SMOS THAT FACILITATE RESEAR CH THROUGHOUT THEIR LARGER SY STEMS Academic Medical Centers T OUTSOURCING for speed been successful without having to focus on these types of operational efficiencies, so it’s not part of their culture,” Dr. Goldberg says. “Ours also is a highly regulated environment, which creates a degree of conservatism about people’s willingness to make changes in the way they do things. In many cases, the benefit of new technologies is really a value proposi tion that is realized over time.” But if the technology is powerful enough so that even one trial out of 100 allows the sponsor and its partner to make the right deci sion to stop a trial early enough when there is a problem or a safety issue, this can have an impact that is measured in millions of dollars. “Part of the technology adoption issue is about how purchasing decisions are made,” Dr. Goldberg says. “This requires an ability to look at the big picture, and to look at the value propositions across an enterprise as opposed to trying to justify the implementation of a tech nology on a trialbytrial basis.” Savvy CROs, SMOs, and AMCs are mov ing beyond the pure clinical aspects of part nering, often forming a series of relationships other than with sponsors. For example, many are differentiating themselves by partnering with IT vendors that provide the software and hardware processes that allow the CRO to bring solutions to the sponsors. “A big part of our strategy is to identify technology vendors in the marketplace that have solutions,” Dr. Goldberg says. “What we can offer is the integration of those technolo gies with the rest of our CRO services, bring ing to bear the experience of having done thousands of clinical trials and knowing how to really make this stuff work in the context of a clinical trial. That skill set is different than being able to generate good software. Whether it’s technology we develop internally or existing technology that we see as bestin class in the marketplace, we make practical use of it in the conduct of our trials.” Portal technologies, including those used by Parexel, are management tools that make data readily available, independent of the place where the user of the system might be located. This technology gives sponsors and their CRO partners the ability to share documents and information required to run the trial, and col lect and make available key metrics, whether it is patient recruitment, site recruitment, or the status of datamanagement activities. Identifying potential safety or efficacy issues can be done much earlier by having realtime access to information. Previously, information was collected piece by piece, and compiled into spreadsheets before being distributed. By the time people received the data, the infor mation was already a week or two old. “Technology allows for faster decision mak ing, and it affects decisions and interventions,” Dr. Goldberg says. “We can recognize prob lems midstream and make the kind of mid course corrections neces sary to keep the trial mov ing. As opposed to only recognizing in the end that there were problems, ultimately causing the trial to drag out.” Remote electronic data capture is another area that could help compress the clinicaltrial process. How ever, it is an area that is not being adopted as quickly as some had hoped. According to ACRP, adoption of technology, particularly that of remote data entry (RDF) would redefine the industry. The association suggested just a year ago that site computerization would be necessary for standardizing and improving data collection and reporting. The thought was that RDF from the site level would grow in an effort to transport data more rapidly and accu rately. In fact, ACRP reports this has not hap pened, noting that there does not seem to be a move toward common standards for remote data entry. The association concludes that con flicting priorities and disagreements about for mat must be resolved before remote data entry becomes commonplace. “We believe that electronic data capture — real time access to information — results in cleaner data, collected faster,” says Cary Gar ner, VP of the Global Clinical Research Unit, at Parexel. “Our metric indicates that EDC can reduce the number of queries, or situations where data are inconsistent, ambiguous, or where things might have been left blank. The query process — or going back to the investi gator for data clarification — is something that has to be tracked very carefully in terms of having those questions answered and then making the changes to the database based on investigator feedback. Handling a query costs in excess of $100 per query generated. Thou sands of queries can be generated during a trial. Eliminating roughly twothirds of those queries through the use of electronic data cap ture is not only an efficiency in terms of cost, but it’s also an efficiency in terms of time. The introduction of that kind of technology ulti mately impacts the ability to close out the database at the end of a trial.” The pressure to develop ways to compress time is certainly not new. Pharmaceutical companies have been talking about doing this for decades. “The advancement in new technologies is really going to play a role in helping the industry actually achieve their compression goals,” Mr. Garner says. “But for that increased speed to occur, there must be an effective strategic and tactical development plan in place at the very front end, in which medical objectives are clear ly defined. All organizations involved must understand what the practical aspects are going to be in the study.” One of the key areas in time compression, whether it be at the beginning of a trial, when a com pany is conducting site selection or patient recruitment, or at the backend, when it is try ing to close out and lock the database so that it can begin statistical analysis, is improving the level of communication between the inves tigative sites and the datamanagement team. With the development of Webbased tools, pharmaceutical companies now have the means to actually achieve some of their objec tives with regard to speeding the clinicaltrial process. But the issue of the individual spon sor’s willingness to make these decisions based on realtime data remains. “Organizations must be willing to accept a certain risk profile versus a reward opportuni ty by having information available earlier, and not all sponsors are prepared to do that,” Mr. Garner says. “Some companies still revert to more conventional standards and processes of clinical development. It’s like any other evolu tion or revolution in the marketplace. There are early adopters and then there are other organizations that are unwilling to bring these technologies into the mix. One of the chal lenges for the CRO industry is to be able to differentiate its services and, in fact, establish value premises with clients rather than cost driven premises.” The Need for Better Patient Recruitment The issue of clinicaltrial efficiency is not only about the speed and accessibility of data, but access to the people that make drug devel opment possible — test subjects. Five years ago, almost half of all study patients were referred to a clinical trial by their physician. Today, nearly twooutofthree patients refer themselves — often by going outside their primarycare network to partici pate in a clinical trial. While this indicates a willingness among some patients to be pro active in dealing with their illness, less than 35 PharmaVOICE M a r c h 2 0 02 A big part of our strategy is to identify technology vendors in the marketplace that have solutions. DR.MARK GOLDBERG T OUTSOURCING for speed “Global registration is becoming more and more desirable for our clients,” Mr. Garner says. “Pharmaceutical companies want to have clinical data from those different geographies if possible, where they might do more mar keting studies in those regions to increase their rate of penetration in those markets.” Achieving peak sales as quickly as possible involves many factors in the clinicaltrial pro cess, including the types of sites selected, the types of protocols that are followed, and ulti mately the amount of clinical work that is done after a drug has been approved. Extending the productlife cycle may mean changing the delivery form of the drug or receiving approval for a niche market or for a pediatric population or specialty population. Expanding claims about a product involves ongoing clinicaltrial activity. As a result, Phase IV research is currently the fastest growing area of clinical spending. In late Phase III/Phase IV studies, pharma ceutical companies may have several objectives, including the comparison of their drug with other drugs already in the market, investiga tion of a drug’s longterm effectiveness and impact on a patient’s quality of life, or to deter mine the costeffectiveness of a drug therapy relative to other traditional and new therapies. “Phase IV is the fastestgrowing segment of trial research and one of the most fragment ed and diverse areas, because it involves so many aspects,” Mr. Getz says. “Phase IV involves outcomes research, pharmacoeco nomic activity, registry trials, patient diaries, and a whole host of activities that are designed to learn more about a drug after it is already being used by the patient population for which it was intended. “I would say this trend started about two to three years ago,” Mr. Getz says. “It took us a while to pinpoint just what the magnitude would be. Extending the product life cycle is an area that companies are just starting to awaken to, which involves ongoing clinicaltrial activi ty, most of which happens in Phase IV.” F PharmaVoice welcomes comments about this article. Email us at feedback@pharmalinx.com. 36 M a r c h 2 0 0 2 PharmaVOICE 10% of the eligible patient population takes part in clinical trials. “The number of subjects that participate in trials within a given disease category is still incredibly low,” says Cindy Dunn, M.D., VP of operations at the Western Institutional Review Board. “The biggest void is public awareness and education. When clinicaltrial news hits the headlines … it’s when things go wrong. Bad news is bigger news, in some respects. Patient enrollment is an enormous publicawareness problem.” To meet this challenge, some pharmaceuti cal companies and sponsors are moving toward communicating directly with, and even part nering with study volunteers. “Pharmaceutical companies are developing relationships with call centers, advertising agencies, Web publishers, and Internetbased patient recruitment matchmaking companies to find more aggressive and more effective ways to reach the patient population,” Mr. Getz says. That need has spawned other outsourcing organizations that focus on matching patients and investigators to clinical trials. For exam ple, Acurian Inc. brings patients and investi gators together by drawing on its key databas es — one of which constitutes 1.3 million patients who have expressed an interest in clinical trials, while another is a database of 41,000 experienced clinicaltrial investigators. (See related story on page 64.) Another company offering patient enroll ment services is Veritas Medicine Inc., whose Website offers a clinicaltrial database that enables patients to be matched to clinical tri als based on confidential information. “The driving force for Veritas Medicine is to improve the quality of care and access to clinical trials for the greatest number of Amer icans battling serious illnesses,” says Joe Avel lone, M.D., CEO of Veritas Medicine. Veritas helps more than 225,000 unique visitors per month review their treatment options and find appropriate clinical trials. Ver itas now provides access to 1,300 clinical trials for more than 100 diseases and conditions being sponsored by the government as well as from partners in the biopharmaceutical indus try. Patients, physicians, and caretakers can reach Veritas Medicine through its partnerships with more than 60 nonprofit disease advocacy groups, healthcare provider organizations, health Websites, and Internet search engines. The Growth of Phase IV Research Twenty years ago, it was not uncommon for sponsors to register in single markets. However, sponsors now are looking to register in a broader base to support the time invested in research. ACURIAN INC.Horsham,Pa.; Acurian is a leading provider of clinicaltrial patient and investigator recruitment solutions for the pharmaceutical and biotechnology industries ASSOCIATION OFCLINICAL RESEARCH PROFESSIONALS.Washington,D.C.; ACRP is an international membership organiza tion that represents more than 16,000 clin ical research professionals from diverse organizations CYNTHIA M.DUNN,M.D.VP of opera tions,Western Institutional Review Board, Olympia,Wash.;WIRB, the oldest indepen dent IRB in America,provides review ser vices in more than 30 countries and in all 50 states SCOTT GRISANTI.Senior VP of business development,eResearchTechnology Inc., Philadelphia.eResearch is a businessto business provider of integrated technolo gybased products and services to the pharmaceutical,medical device,and biotechnological industries CARY GARNER.VP,Global Clinical Research Unit, Parexel International Corp., Waltham,Mass.;Parexel is a leading contract research organization Experts on this topic KENGETZ. President & CEO,CenterWatch Inc., Boston; CenterWatch is a publishing and information services company focusing on the clinicaltrials industry MARKA.GOLDBERG,M.D.President, Perceptive Informatics Inc.,Waltham, Mass.; Perceptive Informatics is the information technology subsidiary of Parexel International Corp. JOHN J. SCHICKLING.Chief financial officer, Phase Forward Inc.,Waltham, Mass. Phase Forward offers eprocess solutions for accelerating global pharmaceutical development THE U.S.NATIONAL INSTITUTES OF HEALTH.Bethesda,Md.,through its National Library of Medicine,has developed ClinicalTrials.gov to provide patients, family members,and members of the public with current information about clinical research studies JOE AVELLONE,M.D.CEO,Veritas Medicine Inc. Cambridge,Mass.Veritas is an online health resource focused on improving patient access to clinical trials and information about therapies in development for serious medical conditions

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