Clinical Services: Managing the Moving Parts By Taren Grom, Editor The Cost of Doing Business The cost of drug development remains on the rise, with most estimates showing that the clinical-trials stage alone accounts for 40% of all costs related to R&D. Our Forum experts discuss best practices that are being employed at their organizations and in the industry to streamline the costs associated with clinical trials. Spector. Wyeth. The cost of drug development is in many ways attributable to the time it takes to get a drug approved and on the market. A number of the major pharma, biotech, and biopharma companies have looked at this issue very seriously and are trying to change the paradigm of drug development. Under the guidance of Wyeth’s President of R&D, Bob Ruffolo, who has been very vocal and proactive about trying to change the whole paradigm, we are examining two areas. One is the overall drug-development process; the other is the clinical space within it. With regard to the overall drug-development process, Wyeth has a series of Springboard Initiatives that are aimed at changing everything we do to get away from the classic 10-year, $10 billion paradigm that often gets quoted in the press with regard to drug development. The most exciting thing we are doing is splitting our development into two primary components. One is called Learn, the other is Confirm. So, the old Phase I, II, III, IIIb, and IV concept is disappearing for us in many ways. We are focused on learning as much as we can about the small molecule, biopharmaceutical, or vaccine that we have under development in the Learn phase, which is a bit like Phase I and Phase II, and in the Confirm phase we are going all out for the registration trials. We are not the only company doing this. To give due credit there are several other companies employing learn-and-confirm strategy variations. The basis for this strategy stems from a paper published by Lou Shiner from the FDA 10 years ago. We are aggressively pursuing this initiative because we think that: one it will increase our success rate with molecules that work; and two, help us limit the investment in molecules that don’t work. Hamilton. Avalon Pharmaceuticals. There are several best practices that can limit costs. One, it is important to pay careful attention to the protocol and CRF design to avoid revisions and changes in scope of work. Next, make sure that the statistical methods are sound and that the sample sizes selected are sufficient to provide statistical power to meet study objectives. Another best practice is to use electronic data capture with flags for immediate identification and revision of queries. Adaptive trial designs are a good way to reduce costs, when appropriate. When possible, conduct virtual investigator’s meetings to follow up on studies when there is mutual familiarity with the physicians. Spector. Wyeth. Learn and Confirm is the big framework for change, and within this there are many things we are doing in the clinical space. Individually each initiative probably isn’t enough, but collectively we hope they make a huge difference in terms of where we select the sites, how we select the sites, the use of large Phase II centers, the use of technology, the selection of ascending markets, the development of protocol synopses earlier, the involvement of sites and key opinion leaders in the development of the protocols, and so on. One of the most important things to consider when talking about the cost of clinical studies is enrollment. Enrollment is to clinical development as location is to real estate. It’s about not only getting patients into trials, but getting quality patients into trials who meet the study criteria and then the long-term retention of those patients. To meet these goals, among the best practices that we employ are better selection of the sites and better prescreening of the clinical investigative sites in terms of their capabilities. This goes beyond just chart review, and includes engaging sites in the early stages of the development of the protocol so we can better understand and they can better understand expectations and hopefully develop protocols that are more likely to enroll patients because they take into account real-world considerations. Also, we are looking at ascending markets where there are large unmet medical needs, and consequently the availability of patients. We also are engaging with early clinical development centers, or ECDCs. These are large centers around the world that have very large numbers of patients in specialized areas. Essentially, we are setting up master service agreements that allow us to work with them in a very streamlined fashion. We have set up 15 of these centers to allow us to conduct Phase II trials very quickly. In addition, because we are working around the world we made a major change in the timetable associated with protocols. The Enrollment Breakthrough initiative, spearheaded by Dr. Michael Smith, VP of Americas research organization, and Mark Ridge, director, global enrollment planning and performance, looked at the timetable associated with gaining approval in various regions around the world. Basically, we are developing a draft protocol synopsis nine months before we enroll a patient. This way we are able to begin to target the regions of the world where we are going to conduct our studies much earlier and consequently file the regulatory documents associated with starting up in those regions much earlier to get as near to simultaneous global enrollment as we can. We want robust starts where we have all of our sites identified up front and all of our site initiations occurring globally in a very short timeframe. One way to ensure this is use a metric that tracks the time it takes from protocol approval until 80% of the sites are up and enrollling. This is a key metric for us. We have another breakthrough program called Site Management, being coordinated by Dr. Michael Smith, VP of the (Wyeth) Americas research organization, under the auspices of Dr. Evan Loh, multitherapeutic head, and Dr. Gary Stiles, Wyeth’s chief medical officer, which is in the early stages of being rolled out. We are very actively looking at how we work with clinical sites and what can be done better. Wyeth recognizes that the site is the face of the company to the patients; and how we work with the site has a significant impact upon our relationships with future prescribers, and therefore how we work with sites is important. Becker. Cytogen. It is always important to spend time up front with clinical sites and investigators to make sure there is a common understanding regarding the intended patient population for a proposed study, the referral patterns and working relationships among investigators at the potential clinical site, and most importantly any other clinical studies that could potentially compete for the same patient population. While streamlining the timelines and thus the cost of individual studies is important, it has always been critical to design clinical studies with well-thought out endpoints that allow, to the greatest extent possible, informed decisions to be made by both the scientific and business viewpoints about whether, and in what direction, to pursue development of drug candidates. Integral Partnerships CROs have become an integral part of successfully implementing a drug-development program. Our experts outline what they look for in a CRO partner. Hamilton. Avalon Pharmaceuticals. We have issued an RFP for CROs’ proposals at the start of our Phase I and at the start of our Phase II developments. We anticipate a similar competitive selection at the start of Phase III studies. Our preference would be to develop a working relationship with a single CRO across all phases of clinical development and regulatory submission. On the other hand, we are re-evaluating our CRO contracts at each step with selection based on performance, reliability, capacity, and cost. Spector. Wyeth. We work with many CROs, which is a very generic term that ranges from specialty organizations that bring in specific expertise around the knowledge of a disease state to knowledge of sites to knowledge of specific technologies or devices to a full range of services. We have taken a preferred provider approach in the past five years to narrow down the number of CROs that we work with. We have relationships with all of the major CROs and we know some are better in some areas than others. We assess their performance on a regular basis. We tend to look at continuing to work with CROs that have good track records with us. Because Wyeth is global and works in 65 regions globally, we are still struggling to find a CRO that can meet all of our needs in a single organization. For this reason, we often have global studies using multiple CROs. Putting Technology to Work Technology in its various forms — EDC, portals, ePRO, etc., is impacting the clinical-development process. We asked our Forum participants to outline the technologies that have been most beneficial to their clinical operations. Becker. Cytogen. Cytogen has benefited from new technologies such as electronic data capture (EDC) and the like, which have helped to eliminate redundancies — thus reducing costs — while shortening the time from the end of a study to the availability of data from the study. Shortening timeframes in this way is important for filing purposes and for planning the next phase of studies. EDC technologies also allow tracking of compliance at clinical sites much nearer to real time so that problems are identified earlier while they can still be resolved. Spector. Wyeth. I believe that IT has been the underpinning of the modern clinical-trial organization. And, strategically, we focused on our IT systems about 10 years ago in terms of how we were going to change trials. The first thing we did that was different from the rest of the industry was to focus on our back office operations. We recognized that the first major component in drug development is about hypothesizing and developing the right protocols. And the back end of drug development is interpreting data and determining if the data validate the hypothesis and learning what the data tell us about the treatment. Everything else in between is about gaining data efficiently and processing it and turning it into useful information. We put a lot of effort into clinical database systems, what we call a global clinical data environment. This involved centralizing, upgrading, and changing all of our technologies and then entering into a major alliance with Accenture, called ACE for Alliance for Clinical Data Excellence. The majority of the back office data processing is now offshore. We also centralized all of the information associated with our clinical trials in one global clinical-trial management system so we have accurate planning and management information about all of our trials. The next thing we did was create an e-clinical portal. The concept is to have the ability to enter data once globally and have it be available to all of the different systems that need it. Our internal systems are highly integrated and they share information about clinical site addresses as well as other information about the protocol. This saves us a lot of redundant work and re-entry work. The other piece was electronic data capture. Five years ago, we developed an internal system that we more than recouped our investment on; now, we are looking at industry-standard systems. Five or six years ago, standards didn’t exist; there were many players pushing many systems. Now that standards are emerging, and we don’t want to be in the IT business, we have to be smart about how we use technology so we are starting to standardize around some of the industry leaders and are looking to go to a second-generation EDC system. For us, technology is now more than just acquiring the data but how we use the data to make good operating decisions about the conduct of the trial. This is very exciting because we can know which sites are having difficulty, what they are having difficulty with, and be able to respond in real time during the trial. It’s not just data capture; it’s about decision making on the go and managing that aspect of the business more effectively. Hamilton. Avalon Pharmaceuticals. The most important technological improvement for the clinical development of new drugs centers around electronic data capture, which can be directly uploaded into the clinical database, which, in turn, serves as the direct link to the eCTD for regulatory submission. Interactive, automated telephonic registration and randomization systems are also a major technologic development but are not applicable to all phases of clinical development. Spector. Wyeth. About 45% of our trials use ePRO. As soon as we started to convert from paper-based trials to remote data capture-based trials, we realized we didn’t want to be gated by the last piece of paper from a diary coming in. So we have been deploying ePRO very aggressively. About 97% of our new studies use EDC and about 45% to 50% use ePRO. We are looking for standardization, we are looking for this component of data capture to coalesce around standards. Right now this area is in an earlier technological stage than EDC; but it’s a lot like EDC was five years ago, with many players and many approaches and we are pushing for standardization. As that occurs, we believe ePRO will become ubiquitous within clinical studies. We also have been very aggressive in establishing metrics for data flow from last subject visit to database freeze. We have standards for critical path studies, for submission-based studies, and so on. It’s almost impossible to hit those timeframes with paper anymore. Going Global By all accounts, clinical trials conducted on a global scale are increasing. We asked our experts to talk about the implications associated with global studies. Hamilton. Avalon Pharmaceuticals. To date, we have limited our clinical development to the United States but recognize the potential that Eastern Europe, India, and Asia provide for rapid study accrual as well as access to earlier stage disease and tumor types not commonly encountered in the United States. Spector. Wyeth. For a number of years, we carefully watched the deployment of the Internet at clinical sites around the world. And when we went to launch our first-generation EDC system we polled sites to assess which were Internet capable. We built into our site selection process IT requirements so that when we do our preliminary site qualification surveys we will already know whether sites have the requisite Web access and PC technology. There are very few regions in the world that do not have good Internet capability. Many countries, even where other parts of the infrastructure aren’t as good, still have excellent Internet capabilities. When looking at global business processes, we have to be respectful and understand the cultural differences with regard to society and business customs. If we are building a clinical program that is truly global and involves multiple regions we need to understand that other countries don’t shut down for Super Bowl Sunday, for example. We need to know that there are different holidays that don’t always coincide with our business schedules and those factors need to be considered. Global studies require a different level of understanding in terms of building a timeline and mapping out a clinical program. Getting Personal Personalized medicine is an exciting field that promises to increase the efficiency of drug development, improve patient safety, and deliver better medicines for unmet medical needs faster and more cheaply. Our experts provide their views on the state of personalized medicine in the industry. Becker. Cytogen. For more than 27 years, Cytogen has been active in identifying and developing products that facilitate personalized medicine by developing two therapeutic products that are paired with related imaging applications. A key component of our strategy is to develop and commercialize targeted oncology agents in areas of unmet medical need. Here’s an example from our product portfolio: bone scans are routinely used to determine when prostate, breast, and other cancers have progressed to the skeleton, which is frequently a very painful condition and may indicate the patient has advanced or aggressive disease. In normal adults, the skeleton is completely broken down and built back up every seven years. When cancer spreads to bone, however, tumor cells disrupt this balanced process and can create either excessive bone formation or destruction. Bone scans work by targeting and illuminating these metabolic sites of imbalance using an imaging radioisotope in connection with a traditional gamma camera. Cytogen’s Quadramet uses the same principle of selectively targeting areas of metabolic imbalance in the skeleton, but it also delivers a therapeutic form of radiation. In cancer patients with a positive bone scan, Quadramet has been approved to treat the pain associated with cancer that has progressed to the skeleton and more than a dozen clinical studies are ongoing to further determine whether it can destroy or delay the progression of cancer in bone. Since Quadramet only targets metastatic bone disease, a positive diagnostic bone scan is required to identify patients likely to receive pain relief from the product — sparing those with a negative bone scan the associated toxicities of the therapy and the healthcare system an unwarranted treatment cost, which is personalized medicine at its best. Hamilton. Avalon Pharmaceuticals. The technologic core of Avalon Pharmaceuticals, AvalonRx, is positioned to support individualized medicine. By evaluating expression of critical genes that are directly related to drug effects and/or metabolism before and after drug administration, patients who are most likely to receive benefit and those more likely to encounter toxicity from drug treatment can be identified. Identifying the most suitable patients for a specific treatment not only improves the efficiency of clinical development but also is best for patient care. Spector. Wyeth. We are doing a lot of pharmacogenomic studies, we are looking at genotyping, we are trying to understand disease, and how disease varies from population to population. We all recognize there is an opportunity to have medicines that treat a narrower population and that are more effective within this population than a broad population. Many companies, Wyeth included, are looking at these underlying factors. Adapting to Adaptive Trials There is a great deal of interest in the area of adaptive trials, which is viewed as a way to accelerate drug development without “breaking the rules.” There are also significant misunderstandings as to the meaning of “adaptive.” We asked our experts for their opinion on this study method and what, if any, impact these types of trials will have on drug-development strategies. Hamilton. Avalon Pharmaceuticals. Adaptive designs are those that use data from early subjects on a study to adjust the treatment of subsequent subjects. There seems to be a degree of peer pressure to employ an adaptive design because it is new or cutting edge, even when it does not offer an advantage over standard Phase I, II, or III designs. To be a valid clinical-trial design, adaptive studies should define the hypotheses to be validated and the rules for “adaptation” before the study start. Spector. Wyeth. From my perspective, adaptive trials are trials that are designed in such a way that without affecting the blinds and based on predetermined criteria can adapt according to preset rules in terms of the conduct of the trial; for example, a dose-ranging study that could optimally enhance enrollment in the arm that is most effective without breaking the blind. Or perhaps a seamless Phase II to Phase III study, which is something that is still undergoing considerable discussion with the FDA. Dr. Michael Krams, assistant VP of adaptive trials, has been driving a multifunctional team within Wyeth to help us implement adaptive trials. We are running adaptive studies and learning from them; in turn we will continue to grow our knowledge of how to execute adaptive trials well.Adaptive trials are changing everything. To be able to make decisions in as near as real time to conduct an adaptive trial, means there has to be rapid data capture, hence EDC. There has to be a sophisticated randomization system that is fully blinded and a statistical design to support the trial that the agency will accept. The logistics of drug supply are changing; in essence, adaptive trials are driving all of us to another place in terms of performance. Adaptive trials are testing all of our disciplines and forcing all of us to rethink the logistics about how we conduct trials. For an adaptive trial, we would like to be able to lock and freeze the database in three days; we aren’t there yet, but we are working toward this objective. PharmaLinx LLC, publisher of the VIEW, welcomes comments about this article. E-mail us at [email protected]. According to an independent analysis, clinical trials conducted by CROs are completed on average 30% more quickly than those conducted in-house. This results in an average time savings of four to five months, translating to between $120 million and $150 million in increased revenue potential. Sources: KMR Group Inc. and Parexel’s Pharmaceutical R&D Statistical Sourcebook, 2003/2004. Even though we’ve made a lot changes in the past several years, as we look to our future plans, we still see considerable opportunities for radical change. Ira Spector Wyeth The CRO market size is estimated at $10 billion and growing. Sources: CenterWatch, World Contract Research Organizations Markets, Frost & Sullivan, 2003 thought leaders n Michael D. Becker. President and CEO, of Cytogen Corp., Princeton, N.J.; Cytogen is a specialty pharmaceutical company dedicated to advancing the treatment and care of cancer patients by building, developing, and commercializing a portfolio of oncology products. For more information, visit cytogen.com. Note: Mr. Becker also is chairman of the Biotechnology Council of New Jersey. For more information, visit biotechnj.org. n J. Michael Hamilton, M.D. Chief Medical Officer, Avalon Pharmaceuticals Inc., Germantown, Md.; Avalon Pharmaceuticals is building a pipeline of better drugs with a drug discovery engine that monitors changes in gene expression (transcription) and exploits this information in the discovery, characterization, optimization, and development of these drugs. For more information, visit avalonrx.com. n Ira Spector. VP, Clinical Development Operations, Wyeth Research, Collegeville, Pa.; Wyeth is one of the world’s largest research-driven pharmaceutical and healthcare products companies with leading products in the areas of women’s healthcare, infectious disease, gastrointestinal health, central nervous system, inflammation, transplantation, hemophilia, oncology, vaccines, and nutritional products. For more information, visit wyeth.com. While streamlining the timelines and the cost of individual studies is important, it has always been critical to design clinical studies with well-thought out endpoints. Michael Becker Cytogen The CRO industry is international. Its leading companies are familiar with regulatory procedures and business practices in a number of countries. CROs employ some 100,000 professionals around the world. They possess high ethical standards and comply with Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) guidelines published by regulatory authorities. They offer clients an unparalleled resource, providing therapeutic and regulatory expertise, nonclinical and clinical drug development experience, and state-of-the-art technology. Source: Association of Clinical Research Professionals CRO revenue is increasing at an annual rate of 14% to 16%. Source: Parexel’s Pharmaceutical R&D Statistical Sourcebook, 2003/2004. Global R&D Outsourcing Market and CRO Share Note: Dollars are in billions Source: A New Global Outsourcing Market Model to 2007, Goldman Sachs, New York. For more information, visit goldmansachs.com. CRO Usage is Associated with Faster Development Times Protocol Readiness to FPFV Protocol Readiness to Study Drug Availability Protocol Readiness to LPFV LPLV to Data Lock Source: Tufts Center for the Study of Drug Development, Boston. For more information, visit csdd.tufts.edu. CRO Revenue Growth Worldwide Note: Dollars are in billions Sources: CenterWatch, Boston. For more information, visit centerwatch.com. Frost & Sullivan, San Antonio. For more information, visit frost.com. June 2007 VIEW on Clinical Services Our preference would be to develop a working relationship with a single CRO across all phases of clinical development and regulatory submission. Dr. Michael Hamilton Avalon Pharmaceuticals CROs are flexible. Their focus on clinical-trial design, implementation, and support allows them to offer single-service components or complete development programs. The industry is evolving toward a full-service model, where CROs offer services from the earliest stages of development through clinical trials and postapproval research. Source: Association of Clinical Research Professionals According to one industry estimate, in 2006 the global clinical-trials sector was valued at about $10 billion with the potential for considerable growth over the next few years. Clinical and drug-development processes have experienced a marked change over the past 10 years, influenced heavily by rapidly evolving technological trends, expansion of clinical trials into global markets, such as Russia, India, and China, and a push for a universal paperless system, which most believe will help improve patient treatment and care. There has also been a broad need to adapt processes amid continuing efforts to implement measures that will help alleviate the ever-growing costs related to R&D, while at the same time maintaining all safety and efficacy standards related to GCP. According to Kenneth A. Getz, senior research fellow at the Tufts CSDD and chairman of CISCRP, biopharmaceutical companies spent $6.6 billion on contract clinical services in 2005, net of pass-through costs, such as central lab fees and investigator grants. The rate of growth in spending on outsourced services by sponsor companies has outpaced the growth rate in overall global development spending — 16% and 11% annual growth respectively since 2001.

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