By Denise Myshko

A greater regulatory focus on safety means companies are under pressure to provide more information about a prescription drug, as well as about the characteristics of patients, once a product becomes available to the larger marketplace. companies are being asked to provide information to physicians, patients, payers, and regulators about how products are used, the effectiveness in certain patient populations, and whether there are safety concerns. Phase IV trials have become important vehicles for postapproval risk management and drug-safety assessment. Additionally, Phase IV studies can be used to assess comparative efficacy, health outcomes, and health economics — all of which can be important data for marketers looking to exalt differentiation in the marketplace. Thought Leaders Carol Collins. Corporate VP, Peri-Approval Clinical Excellence (PACE) Global Group, Parexel International Corp., Waltham, Mass.; Parexel is a global biopharmaceutical services organization, providing a broad range of knowledge-based contract research, medical marketing, and consulting services to the worldwide pharmaceutical, biotechnology, and medical-device industries. For more information, visit parexel.com. Paul Colvin. Director, Clinical Operations, Eli Lilly and Co., Indianapolis; Lilly is developing a growing portfolio of first-in-class and best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. For more information, visit lilly.com. William H. Crown, Ph.D. President, i3 Innovus, Basking Ridge, N.J.; i3 Innovus, a division of i3, provides health economics and outcomes research solutions that use thought-leading analyses and the largest, most complete longitudinal database available to support market access and reimbursement of healthcare products. For more information, visit i3innovus.com. Mario Ehlers, M.D., Ph.D. Chief Medical Officer, Pacific Biometrics Inc., Seattle; PBI provides comprehensive laboratory services in support of pharmaceutical and diagnostic product research. For more information, visit pacbio.com. Bruce Freudlich, M.D. Assistant VP, Musculoskeletal Clinical Research and Development, Wyeth Pharmaceuticals, Collegeville, Pa.; Wyeth is one of the world’s largest research-driven pharmaceutical and healthcare products companies. For more information, visit wyeth.com. Richard Gliklich, M.D. CEO, Outcome, Cambridge, Mass.; Outcome is a provider of strategies and solutions designed to meet the unique needs of the postapproval market. For more information, visit outcome.com. Doug Kurschinski. VP, Market Development, AtCor Medical Inc. (USA), Lisle, Ill.; AtCor Medical develops and markets cardiovascular technologies for risk assessment and patient management. For more information, visit atcormedical.com. Peggy Schrammel. Executive Director, Late Phase Development Division, PharmaNet Inc., Blue Bell, Pa.; PharmaNet is an international drug development company offering a complete range of clinical development and consulting services to the pharmaceutical, biotechnology, and medical-device industries. For more information, visit pharmanet.com. Donald Therasse, M.D. VP, Global Medical Affairs, Eli Lilly and Co., Indianapolis; Lilly is developing a growing portfolio of first-in-class and best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. For more information, visit lilly.com. Gary Tyson. VP, Clinical Development Practice, Campbell Alliance, Raleigh, N.C.; Campbell Alliance is a specialized management consulting firm serving the pharmaceutical and biotechnology industries. For more information, visit campbellalliance.com. Cynthia Verst-Brasch. VP, Late Phase, Kendle, Cincinnati; Kendle is a global clinical research organization, delivering innovative and robust clinical-development solutions — from first in-human studies through market launch and surveillance — that help the world’s biopharmaceutical companies maximize product life cycles and grow market share. For more information, visit kendle.com. April 2006 Forum Dr. Donald Therasse Eli Lilly and Co. One of the challenges with a global Phase IV trial is to get harmonization of the protocol. Cynthia Verst-Brasch Kendle Because there is more intense competition in the marketplace with me-too products as well as shrinking patent lives, there is a real push for life-cycle management; as such, companies realize that they have to get out there with Phase IIIB/IV studies. Dr. Bruce Freudlich Wyeth Pharmaceuticals We believe that it takes a large number of patients studied in the postmarketing period to create a strong safety database for our products. Phase IV Trends There is much more emphasis on — and more postmarketing requirements for — Phase IV studies, especially to learn more about the safety of a drug and how it is used in clinical practice. Crown. More emphasis is being placed on Phase IV studies than ever before. The types of studies vary widely from analyses of health insurance claims data — primarily in the United States — to patient registries, prospective patient surveys, and large, simple clinical trials conducted globally. Changes in the marketplace for pharmaceutical products are creating the need for much more information about the characteristics of patients and less emphasis on physician information. Companies must be proactive in monitoring the performance of their products in actual clinical practice. In the case of safety-related issues, for example, it is important to identify safety signals as soon as possible to limit adverse patient outcomes. In addition to being good for patient care, it is a smart business decision to limit any liability that might result from serious adverse events. Schrammel. The overall science behind Phase IV trials has come a long way. Patients, providers, and payers are making sure that science leads development and ultimately supports effective marketing. Interest in using patient registries as a late-phase tool continues to increase. Patient registries are larger, more observational studies designed to determine patient outcomes in a natural setting. These registries go hand-in-hand with another trend: pharma’s commitment to using Phase IV tools for risk-management purposes. Certainly with some of the guidances that have been issued by the FDA and the European regulatory bodies, pharma is looking at what the risk-benefit ratios are for products on an ongoing basis. Long-term safety endpoints are rising to the top of importance in late-phase studies. Some of the data that we have seen show that up to 80% of the drugs approved in the United States are required to fulfill some type of postmarketing obligation, whether it is evaluating the impact of the drug in a special population or tracking the long-term safety associated with the drug. Pharma companies have to step up and meet those commitments. Freudlich. It is encumbant upon us to understand how our products are being used and if there are differences in safety or efficacy in different populations. For example, we want to know if medicines work differently in patients who are being treated for early-stage diseases, late-stage diseases, or in patients with comorbid conditions. It is also important at times to examine specific patient subsets, such as elderly patients. We occasionally are interested in making comparisons with other medications on the market, which can help give authorities and consumers some indication of differences in value. We’re very attuned to safety. We believe that it takes a large number of patients studied in the postmarketing period to create a strong safety database for our products. This may be useful, for example, to uncover adverse events that are rare, which may not be evident from the few thousand patients who have been studied for drug registration. Crown. Because Phase IV is the first opportunity to observe a drug’s use in standard clinical practice, it also is the first chance to observe the impact of a product upon medication adherence and switching patterns, use of healthcare services, and drug safety in large numbers of patients who often have other comorbidities and who are being treated with concomitant medications. Schrammel. Where Phase IV can really shine is looking at nontraditional endpoints, such as economic value, treatment satisfaction, quality of life, compliance, and caregiver burden, as well as more intangible benefits that are important to patients but are very hard to get in a Phase III environment. Colvin. Phase IV trials extend the work that has been done leading up to registration. The registration package is broad, but it certainly is not complete in defining appropriate use of that molecule in practice. There are a number of activities that we look at depending on the product, such as combination therapies, sequential therapies, and comparative efficacy; additional health outcomes or health economics; safety studies; and new populations. This expands the database that helps us define appropriate use and guide physicians. Schrammel. There has been more continuity between Phase II, Phase III, and Phase IV trials in the last couple of years. There used to be silos in those sectors, but those walls are coming down. Events of the last couple of years have forced us to look at development and life-cycle management in a different way. Therasse. We are focusing on high-quality medical studies. We’re doing more safety studies, but the trials really depend on the product and what the FDA’s postmarketing requirements are. There is better life-cycle planning in general for molecules — extending to the global medical planning and the coordination of what was done in Phase III and what needs to be done in Phase IV. Gliklich. One of the big changes is more focus on credibility and standardization; the evolution of standards in this arena is happening very quickly. With regard to investigational studies, there’s more clarity on what’s necessary in certain protocols involving human subjects. But there are still open issues regarding how to select sites, how to select investigators, and how to determine sampling criteria. On the observational side, there’s currently work going on under the Agency for Healthcare Research and Quality (AHRQ) to create a reference handbook from a broad group of stakeholders to guide how to evaluate information from these types of programs. The quality from these studies needs to be much more consistent. Achieving Optimum Outcomes Experts interviewed for this Forum stress that companies can achieve positive outcomes in Phase IV by designing appropriate studies, asking relevant medical questions, and increasing the value to the sites. Freudlich. As a company, we don’t believe in study designs that only aim to place more patients onto our product. Instead, we expect to enhance our knowledge of the clinical science behind our products and to understand how the drugs work in the different populations. Getting the study design right is an important first step. We seek outside expert advice to test and develop our ideas. We may have what we consider great ideas about a study concept or design; but if the best opinion leaders in the field think that they don’t make sense or are inconsequential, we won’t go forward. It is also important to keep an eye on the study as it’s proceeding, which involves having an excellent clinical-operations team that is well trained and is in close contact with all study sites. Additionally, there needs to be frequent feedback; this way if any difficulties arise along the way, adjustments can be made. Verst-Brasch. If the resultant clinical data are for a nonregistrational purpose, in other words, the intended recipients are not regulatory authorities, we can offer creative study design and operational elements to render high-integrity data that are compliant. Collins. It is important to have a joint team with all of the different stakeholders within the company involved — not only the R&D group but also the marketing group, outcomes research, pharmacovigilance, and so on, who meet around the table to understand the products and the markets. Everyone needs to agree on the protocol design, with a focus on what is needed rather than collecting unnecessary data. Schrammel. Companies should take the time to think through the issues and define them so that when the study is designed, everybody has a solid understanding of what it can and can’t do. People have different perspectives and expectations; so before the study begins, it’s important that all of the stakeholders understand what they’ll get back. Therasse. Another challenge is getting investigators to take Phase IV studies seriously. Sometimes when the shine wears off of a new product, investigators may not be as interested in doing the work, particularly if the research does not address an important medical question. Gliklich. The best way to compete for sites for a Phase IV program is to increase the value of what is delivered to the sites. There has to be value brought back to the sites. Collins. Technology is one reason why the Phase IV area is growing at the rate that it is. After many years, electronic data capture has finally been accepted as the most efficient method when conducting large studies with thousands of sites in multiple countries. Tyson. Technologies such as EDC can be helpful in large-scale registrational studies. There are some very specialized EDC vendors that focus on these large-scale registrational studies, making their products extremely easy to use and requiring minimal training for clinical staff. That significantly improves the overall efficiency of the entire registrational study. Phase IV Challenges Recruiting physicians and patients, managing large global studies, and collecting and managing data are some of the challenges sponsors face. Ehlers. Conducting large Phase IV studies can require thousands of patients and can take many years. Some mortality and morbidity studies can be as large as 20,000 patients over five years. This can exhaust the supply of patients willing to participate in the United States and Europe, and the length of the studies can consume a significant portion of the drug’s patent life post approval. Gliklich. These programs tend to use sites that are potentially the customers of the sponsor, so there are more dynamics in play. The biggest challenge is that, as these programs get larger, they need to compete with each other for sites to participate. Ehlers. Increasingly, there will be the need to incorporate tests for genomic and proteomic markers in Phase IV studies to better understand pharmacogenomic and proteomic properties of drugs. This will present challenges in terms of how to deploy such tests on a big scale and how to interpret the results. Crown. A major challenge with Phase IV studies is the need to control for the myriad other factors, besides drug treatment, that can influence patient behaviors and outcomes. Large, simple Phase IV trials that are specifically designed to measure health-economics and outcomes-research endpoints probably do the best job in this regard. But because such trials are expensive to undertake, nonrandomized study designs are more common. These can provide reliable evidence, particularly with careful use of sophisticated, multivariate statistical methods. In general, the more robust the data-collection effort, the better the job that such methods can do in controlling for confounding factors, such as unobserved disease severity, that may be the real reason behind variation in patient outcomes. Gliklich. More than 50% of Phase IV programs are global, and more than 50% involve more than one language. Those challenges are obviously different from those of a small Phase IV trial at a single site in Ohio. There are cultural differences; there are regional differences. The relevance of the data is going to differ slightly from country to country; maybe subsets of data will be of particular v lue in France or China. Companies need to be able to produce and manage these studies with different flavors for the different regions and yet still be able to do them in a centralized way for cost efficiencies. Therasse. One of the challenges with a global Phase IV trial is to get harmonization of the protocol. Practice patterns differ around the world. In that way, Phase IV trials are just like Phase III trials. Collins. Very often when doing Phase IV there will be a core protocol with local adaptations. These studies are more complex. There are more stakeholders involved; it’s not just the local marketing company, the opinion leaders, and the physicians in that region. Central headquarters is involved; different regulatory authorities are involved; and there may be other bodies, such as NICE in the United Kingdom, that are looking for more evidence-based medicine. Freudlich. Recruitment is sometimes a challenge because the product is already on the market. Patients can get the product from their doctors, and if it is covered by insurance they are often reluctant to enter a study, especially if a placebo is involved. It is advantageous to spread Phase IV studies out over multiple countries and involve multiple doctors’ offices. This increases the heterogenity of the study population and allows for better generalization regarding conclusions. Data gathering is another challenge but is continually improving with updated technology. EDC is changing our lives. Instead of having hundreds of thousands of pages per study, the entire data set can be viewed in an electronic file. This is a tremendous advantage. Phase IV Outsourcing Trends More Phase IV trials, as well as the individual components of those trials, are being outsourced. Experts say this trend is likely to continue. Schrammel. In the last five years, we have witnessed an increase in outsourcing of, as well as spending on, postmarketing studies. Some statistics indicate that there has been an increase of between 20% and 23% in the outsourcing of this sector. Verst-Brasch. Many companies are continuing to outsource, and those companies that traditionally did not outsource their Phase IV trials are now doing so primarily because of resource crunches. This can be due to financial constraints as well as timing constraints and longer review periods around the globe. Additionally, because there is more intense competition in the marketplace with me-too products, as well as shrinking patent lives, there is a real push for life-cycle management. It’s all about timing. As such, companies realize that they have to get out there with Phase IIIB/IV studies. They are turning increasingly toward CROs for advice and consultation regarding study design and creative operational solutions. Freudlich. Wyeth does all of its Phase IV studies in-house. These studies are so important to the company that we want to maintain as much control as possible to guarantee they are done right. Gliklich. I see more components being outsourced. The rigor that is required, as well as the globalization and the changing technology, are all rarely contained within the medical affairs or even the clinical departments. Most companies typically don’t have all of the components in-house to do these types of studies because of the number of different factors — from site recruitment to site management to data management — involved in Phase IV studies. Collins. Companies are looking to CROs that have developed expertise with Phase IV. Some have this expertise in-house, but we’ve been approached by a number of companies that don’t. Verst-Brasch. Our operational staff members undergo training to understand the basic needs of community-based practitioners who are participating in clinical research. We train our project specialists to do the heavy lifting on behalf of these doctors. They prepopulate forms. They work collaboratively with the physicians and office staff to make it simple from study start up to data collection, data query, and finally site wrap up. They’re trained personnel who become ambassadors and who liaise between the sponsor and the site. The underlying key to success is to ensure that the practitioner’s daily routine is not interrupted while participating in late-phase research. Ehlers. For contract organizations, including CROs and central labs, Phase IV studies offer significant revenue opportunities. Global CROs and central labs will benefit the most because Phase IV studies will mostly be global — increasingly in Eastern Europe, Russia, China, India, and South America — to recruit the patients needed to complete them. Specialty labs also will benefit because of the need for novel biomarker testing. As novel biomarkers are introduced there will be opportunities for vendors with expertise in development of such markers — not only for use in Phase IV trials but for further development and eventual approval of novel tests, such as in vitro diagnostics, that can be used to predict and monitor drug efficacy and safety in targeted populations. Marketing Implications Regulations now require Phase IV studies to address scientific questions, and those interviewed for this Forum say what is good for patients is good for marketing. Schrammel. Up until fairly recently, it was quite common to see single-arm trials in which the unwritten goal was to get as much of the drug into the key prescribers’ hands. Many times, there wasn’t a protocol; there weren’t any scientific research questions associated with the trial. Recently, a couple of things have have happened. Physicians have become more savvy, and patients are a lot more vocal. The scientific community as a whole has said the data that companies are culling through Phase IV have to be scientifically based. There has to be a research question; there has to be a protocol; there have to be metrics; and the data have to be analyzed correctly. Verst-Brasch. Phase IV trials are no longer purely marketing studies. It is no longer permissible from both a local and global perspective to conduct seeding studies since ethics committees, such as MRAC, and regulatory guidelines, such as the EU directive, no longer permit them. Tyson. The goal of Phase IV studies is not to gather marketing data. These studies are conducted to gain additional scientific knowledge. Schrammel. The operative word here is “marketing.” That word makes people uncomfortable when coupled with the words “clinical research.” I look at Phase IV as a way to better characterize a product so it can be used in the most optimal way to benefit patients. Crown. Data collected in Phase IV enable the product to be compared with competitor products, as well as to examine stratifications of the market. For example, a manufacturer with a new product indicated for treating major depression could profile the characteristics of patients treated with its product versus patients treated with other antidepressants already on the market. Phase IV studies can answer a variety of questions. What are the medical and mental health comorbidities of patients treated with one product versus those of the competitor treatments? What is the pattern of healthcare use in the year before treatment and in the year following treatment? Is there evidence that sicker patients are being treated with the new product? The list of questions goes on and on. Answers to these questions help biopharmaceutical firms understand which patient subgroups are likely to benefit most from treatment with their products. Ehlers. For pharma and biotech, successful Phase IV studies can considerably strengthen the drug or biologic in the market by enhancing the safety database, providing useful marketing data versus competitor drugs, and allowing for label extensions and expanded indications. Therasse. These studies are done to answer important medical questions. What’s good for patients is good for business. The results of a good Phase IV trial, just like a good Phase III trial, can be used in the pursuit of advancing healthcare. PharmaVOICE welcomes comments about this article. E-mail us at [email protected]. A Case Study: Phase IV Can Impact Product Positioning Phase IV trials have become increasingly important as competition has intensified in the pharmaceutical industry. By documenting specific mechanisms of action, these studies have the potential to create product differentiation and extend product life cycles, independent of patent life and generic drug development. This is especially true when a Phase IV trial can document an advantage that is not known — or has not been demonstrated — to be a class effect. In one of the more dramatic developments in recently reported major drug trials, Pfizer was able to demonstrate product differentiation for its calcium channel blocker, amlodipine, by using new technology to noninvasively demonstrate differential reduction of central blood pressures. The Conduit Artery Functional Evaluation (CAFE) study — a 2,199 patient substudy of the Blood Pressure Lowering Arm (BPLA) of the 20,000-plus subject Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) — was designed to assess whether central blood pressure effects were different from those measured in the arm by the traditional blood pressure cuff. The ASCOT BPLA compared the amlodipine with the beta blocker atenolol to assess effectiveness of blood-pressure reduction and improvement in cardiovascular outcomes. The CAFE study took on added importance when the ASCOT study was stopped early because of the significant reduction in adverse cardiovascular outcomes in the amlodipine arm as compared with the atenolol arm. The two study arms showed no statistical difference in brachial cuff blood pressure reduction, which therefore provided no clue as to the difference in outcomes. 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