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Improving prescription drug safety and oversight have taken center stage both within Congress and with regulatory authorities. Postmarketing research is an important element of commercialization that enables companies to expand existing markets, enter new markets, develop and deliver messaging that directly compares their products with the competition, and secure a niche position in crowded markets. While the industry’s drug manufacturers and regulatory authorities have always focused on the safety of prescription drugs, experts agree that more needs to be done to ensure the health and safety of the American people. Pharmaceuticals have inherent risks by virtue of their chemical composition. Therefore, the goal is to mitigate those risks as much as possible and appropriately and clearly communicate side-effect profiles. This is particularly important given the hundreds of thousands of Americans who are hospitalized because of adverse events; in 2004, according to the Centers for Disease Control and Prevention, the number of people who were admitted to emergency rooms totaled more than 743,000. Industry leaders agree that drugs have some side effects and that it’s important to weigh a drug’s benefits against the risks. “The industry needs to establish what defines a safe drug,” says Gregory V. Page, Ph.D., FDA practice leader at Deloitte & Touche USA LLP. “A safe drug is not necessarily a drug that doesn’t hurt anybody. There has been a knee-jerk reaction to all the sensational headlines around the dangers of some drugs.” He says regulators, the scientific community, and the industry need to define a standard by which to evaluate the safety of drugs. A Market Correction A move to define a workable formula or protocol has been ongoing. Regulators and legislators have been working to address safety in a postapproval environment when most drugs are available to mass audiences outside a controlled clinical setting. Both the Senate and the House of Representatives have passed bills that would require the FDA to actively monitor the safety of drugs on the market and require pharmaceutical companies to develop plans to manage any serious risks associated with new medications. On July 11, 2007, the House of Representatives passed the FDA Amendments Act of 2007, establishing a new program within the FDA to monitor the safety of drugs after they have been approved and marketed. The bill also includes other measures to enhance drug safety, including increasing the penalties for drug companies that violate safety standards. The Senate bill, approved May 9, 2007, addresses several issues, including renewal of the Prescription Drug User Fee Act (PDUFA), medical-device marketing, pediatrics, and drug safety. Within the drug-safety arena, the legislation includes provisions for active surveillance as a way to respond to and adapt to safety information. The bill would require companies to prepare a risk evaluation and mitigation strategy, as well as a pharmacovigilance statement that addresses whether current safety surveillance is sufficient to assess risks and to identify unexpected serious risks of a drug. Senator Edward M. Kennedy (D. Mass.) and Senator Michael B. Enzi, (R. Wy.) were the chief sponsors of the Senate bill. Congress is now working on a compromise bill. “The Kennedy and Enzi bill will allow the FDA to significantly improve its processes and its ability to enforce safety-related issues,” says Nayan Nanavati, VP, peri-approval clinical excellence, Americas, Parexel International. “This bill is a reasonable proposal. It adds a new order to improve drug safety and it restores confidence as it gives the agency authority to take actions against noncompliance. It also allows the agency to outline, prior to a product’s approval, all of the elements to evaluate and monitor the safety of a marketed product, thereby restoring the public’s confidence in the process.” If this becomes law, the impact will be significant, says Jeffrey J. Stoddard, M.D., VP of medical and scientific affairs, risk management and postmarketing programs, at Covance Inc. “The Enzi legislation would require companies to have a pharmacovigilance plan or pharmacoviligance statement that explains and justifies that standard adverse event reporting is adequate to identify any unexpected risks for a particular drug,” he says. “If the standard practice is not enough, sponsors will be required to identify what additional steps have to be taken.” The bill now empowers the FDA to work together with a new drug sponsor to develop a REMS (Risk Evaluation and Mitigation Strategy) before approval to obtain the necessary safety information about each unique new drug or indication, says James D. Esinhart, Ph.D., executive VP, biometrics and late phase, at Chiltern International. “The bill also provides a structured dispute resolution process intended to bring fairness, timeliness, and finality to the response to new safety information,” he says. This bill is not a crisis for the industry, says Gerald A. Faich, M.D., senior VP of epidemiology and risk management at United BioSource Corp. (UBC). “There already was a movement toward postmarketing commitments and greater accountability,” he says. “This bill will push this movement. This is an effort to further empower the FDA.” There are some concerns, however, about the Senate bill, Mr. Nanavati says. “In particular, there are questions as to what impact the bill would have on the FDA’s day-to-day operations,” he says. “For example, there are some concerns about whether introducing REMS programs will unnecessarily slow down the drug review process and place unreasonable deadlines and financial burdens on the agency.” Developing a pharmacovigilance plan and risk map to potentially detect signals post-licensure is a serious undertaking, Dr. Stoddard says. “Such an undertaking involves looking at the integrated summary of safety for the product and understanding its safety profile, including its mechanism of action and its class, as well as being willing to evaluate whether there are potential unexpected adverse events,” he says. “We need to understand the baseline rates of that untoward event, whatever that might be, so that we can predict how many people may develop the adverse event by chance alone in order to properly interpret postmarketing safety data.” But Dr. Page says the bill may not be enough. “My understanding of the bill is that the maximum penalty for noncompliance is $2 million, and I don’t think that’s enough of a disincentive for most big pharma companies,” Dr. Page says. “I think a structured, time-based escalating penalty with significant dollars attached is what’s needed to get the industry to comply. I think there should be penalties for companies that don’t meet their postmarketing or timeline commitments.” Regulatory Efforts The FDA’s efforts to address postmarketing safety fall into three areas: strengthening the science that supports the FDA’s medical product safety system; improving communication and information flow among all stakeholders; and improving operations and management to ensure implementation of the review, analysis, consultation, and communication processes. The agency’s drug-safety policy is evolving, Steven Galson, M.D., director of the Center for Drug Evaluation and Research at the FDA, said at the June 2007 annual meeting of the Drug Information Association (DIA). “One of the driving forces in drug safety is having the ability to harness the potential of emerging science and technology to develop the tools to implement change,” he said. “This is often what’s missing from these discussions.” FDA initiatives include developing new scientific approaches to detecting, understanding, predicting, and preventing adverse events; developing and incorporating new quantitative tools in the assessment of benefit and risk; and conducting a pilot program to review the safety profiles of certain newly approved drugs on a regularly scheduled basis. “The FDA’s most recent effort is the formation of a new advisory committee designed to counsel the agency on how to strengthen the communication of risks and benefits of FDA-regulated products to the public,” Paul J. Seligman, M.D., M.P.H., associate director for safety policy and communication at CDER, said during an interview. “We needed a greater consumer voice from outside the agency to bolster our efforts in communicating information that is valuable to consumers about all of the products that we regulate. We also needed a venue where we could bring in experts in the science of communications to give us the best advice on how to make our communications efforts world class.” The Risk Communication Advisory Committee will help the FDA better understand the communication needs and priorities of the general public; advise the FDA on the development of strategic plans to communicate product risks and benefits; and make recommendations about crafting risk and benefit messages, as well as how to most effectively communicate specific product information to vulnerable audiences. The advisory committee, made up of 15 voting members, will include experts and public members who are not affiliated with the FDA. Experts will include authorities who are knowledgeable in the fields of risk communication, social marketing, health literacy, cultural competency, journalism, bioethics, and other relevant behavioral and social sciences. “The hope is that either later this year or early in 2008, the committee will be ready to meet and consider many of the interesting and challenging communication issues that we’re constantly facing,” Dr. Seligman says. “Once a drug is approved and on the market, we’re always learning new information about how the product works, particularly among populations who were not studied during clinical trials, in circumstances that weren’t studied during trials, or other things that weren’t considered during the trials,” he says. “Because the drug-development process is dynamic, it’s essential that as new information becomes available it’s communicated widely in a balanced, sensible way so that people can make appropriate decisions about using these products.” The new Risk Communication Advisory Committee stems from the Institute of Medicine’s (IOM) September 2006 report, The Future of Drug Safety: Promoting and Protecting the Health of the Public. The IOM found that the drug-safety system is impaired by the following factors: serious resource constraints that weaken the quality and quantity of the science that is brought to bear on drug safety; an organizational culture in CDER that is not optimally functional; and unclear and insufficient regulatory authorities, particularly with respect to enforcement. The report recommended that Congress enact legislation establishing a new advisory committee to address how FDA communicates information about the efficacy, safety, and use of drugs and other FDA-regulated products. In January 2007, the FDA announced initiatives to address recommendations offered by the IOM report. Industry Efforts “Most sponsors are actively using clinical-trial registries, clinical-trial result databases, or other innovative mechanisms for gathering large amounts of data for new drugs,” Dr. Esinhart says. “The sponsors we work with are moving swiftly to meet their postmarketing commitments.” Pfizer Inc., for example, announced in May 2007 that it has launched an online site to provide up-to-date, user-friendly information on the status of its U.S. postmarketing commitments. This initiative is the first of its kind for a pharmaceutical company. The Website provides study descriptions and status of U.S. FDA postmarketing commitments, current due dates, total listed Pfizer postmarketing commitments, and general information about the process. “From a medical compound’s discovery, through its development, and for as long as it is prescribed, each of our medicines undergoes thorough safety and efficacy monitoring and evaluation in collaboration with health authorities around the world,” says Pfizer’s Chief Medical Officer Joseph Feczko, M.D. “This kind of transparency helps encourage patients to ask their physicians about treatment options. When these conversations happen, they often help patients better understand the risks and benefits of different treatment options.” The FDA first posted a database of all the industry’s postmarketing commitments on its public Website in 2003. The new Pfizer site expands the information available, presented with user-friendly search functions, a glossary of terms, and frequently asked questions about postmarketing commitments. Users can view Pfizer’s regulatory commitments for medications by product name, approval date, and study status, among other criteria. Pfizer updates the site weekly. While drug developers over the past six years have increased the number of postmarketing studies they conduct on newly approved medicines, sponsors believe that those studies have contributed little to their understanding of safety, efficacy, or quality, a recently completed assessment by the Tufts Center for the Study of Drug Development (CSDD) shows. According to the Tufts CSDD survey, 68% of clinical-study sponsors and 79% of nonclinical study sponsors said results contributed either marginally or not at all to their understanding of the safety, efficacy, or quality of their product. But 32% said clinical studies significantly or very significantly increased their understanding of their products. More than half of all postmarketing studies, for which final study reports were submitted, were finished by their projected completion date, Tufts CSDD found. But 45% were delayed because of enrollment problems, technical difficulties, additional FDA requirements, or sponsors expanding the scope of their own studies. At an annual growth rate of 23%, industry investment in postmarketing research is expected to top $12 billion in 2007, according to Cutting Edge Information. A changing regulatory environment, growing concerns about the safety of new medicines, and various uses for large-scale, real-world data on marketed drugs’ safety and efficacy are primary drivers of the growth in the Phase IV research environment today. “FDA’s monitoring of postmarketing safety of drugs has garnered intense criticism from Congress and consumer groups in recent years, especially after Vioxx was pulled from the market in 2004,” Mr. Nanavati says. “The public was exposed to the gaps that were in the system at the FDA and the regulatory constraints that the FDA has in terms of its enforcement of these types of safety issues.” The industry has not done a good job of following up on its commitments to conduct and report on postmarketing data, Dr. Page says. “Postmarketing commitments are just not taken seriously, and the industry hurts itself by not doing these studies,” he says. “They made the commitment and they have to provide the resources. I think there is a rationale for providing some type of incentive, whether it be positive or negative, to make the industry comply with these commitments.” There continues to be a lack of clarity regarding postmarketing surveillance, agrees Patricia A. Steigerwald, MS, RN, VP, global late phase, at Kendle. “The issue continues to be lack of clarity as to what the guidance is going to mandate,” she says. “That’s always a difficulty in not having a clear understanding of what exactly is going to be expected.” Mr. Nanavati says there is room for improvement in meeting postmarketing commitments, but a better regulatory framework is needed. “The regulatory framework, or the guidance document as to how to conduct late-phase studies, is probably less than optimal and it needs to be improved,” Mr. Nanavati says. “Right now, there is a great deal of variation from company to company as to how they approach the conduct of late-phase studies. More cohesive documents by the agency are warranted.” PharmaVOICE welcomes comments about this article. E-mail us at firstname.lastname@example.org. Best Practices: Designing Risk-Management Programs Be Specific: Design risk management programs with specific program objectives in mind. Minimize Complexity: The program must be operational for all stakeholders, including physicians, pharmacists, and patients. Leverage Automation: Provide the optimal benefit by leveraging automation where appropriate. Source: Jeffrey Stoddard, M.D., Covance Inc., Princeton, N.J. For more information, visit covance.com. Dr. Jeffrey Stoddard Covance All drugs have some side effects. It’s important to understand these in the context of the drug’s benefit and to make sure that all stakeholders adequately comprehend the information. Patricia Steigerwald Kendle The bills are an important first step in helping to outline and identify the need for continued surveillance and drug safety once new products are approved. Sound Bites from the Field PharmaVOICE asked experts to outline what the challenges are for conducting postmarketing studies and How the industry and its suppliers can better address concerns about drug safety. Jeff Trotter is Senior VP of Icon Clinical Research, Lifecycle Sciences Group (formerly Ovation Research Group), North Wales, Pa., a global provider of outsourced development services. For more information, visit icon.com. “In my experience, the greatest challenges are in design and execution. Although these are rather broad and basic concepts, they represent very fundamental hurdles that, for many companies, are quite difficult to surmount. While always striving for good science and methodological rigor, postapproval studies can neither be designed nor implemented using a pre-approval template. Postapproval studies must be designed with specific strategic goals in mind. For example, a key initiative could be the development of ‘real world’ data on a newly launched product’s clinical, economic, and humanistic performance. The strategic rationale for this study would be the use of these data to help communicate the product’s value to important market decision makers. If the ultimate goal is to persuade a decision maker of a particular conclusion, then a focus on the elements of persuasion — what it will take to convince the decision maker — needs to be the foundation for the study’s design. This does not and should never compromise science; ideally, it simply focuses the science in the appropriate strategic direction. Because postapproval strategy shouldn’t be compromised either. A study’s strategic foundation also will drive its execution, or more specifically, how the study should be managed. A ‘real world’ postmarketing study cannot be burdened by the same operational approach that would be appropriate for a pre-approval clinical trial. For example, a ‘traditional’ monitoring goal may be to examine adherence to a study protocol. In a postapproval observational study, this is almost a contradiction in terms, as the protocol may dictate very little. Starting with the why and then focusing on the how can help surmount the postapproval challenges.” Rich Vachal is Director of Operations at XTrials Research Services Inc., Somerset, N.J., a full-service CRO. For more information, visit xtrials.com. “Postmarketing studies are typically deployed to add scientific support to a wide range of new commercial value propositions. These include demonstrating non-inferiority of products vis-à-vis competitors, identifying new treatment indications and patient populations, supporting advantageous labeling changes, and evaluating health utilities for formulary, reimbursement, and other economic considerations. Each of these late-phase targets shares the common challenge of ensuring that high-quality study designs are conducted with scientific rigor and efficiency while optimizing the expenditure of research funds to yield the greatest boost in commercial benefits. But strategies to extend an approved therapy to additional indications and patient populations can present product teams with a special set of challenges and business risks. A struggle emerges between pursuing the potential of greater product revenue and avoiding going after new indications that cause additional safety concerns. Putting drugs into patients other than those for whom they were approved can be fraught with unexpected pitfalls. One death in a higher risk population can cause significant concerns for the population for which it was approved. A key challenge then is to accurately assess the impact that pursuing these ‘birds in the bush’ will have on the one firmly in hand.” Jeff Williams is CEO of Clinipace Inc., Research Triangle Park, N.C., a clinical research software company that provides a single, integrated data capture and study management platform for postapproval research and registries. For more information, visit clinipace.com. “A major challenge in conducting postmarketing studies is getting corporate commitment at all levels, all the way to the executive suite. The most important driver is public safety, but companies also should be investing in postapproval studies to protect their franchise of marketed products. Without continual monitoring, it’s like building a million dollar house in Hurricane Alley but then failing to insure it. Companies have a fiduciary responsibility to protect themselves and their shareholders from the unforeseen adverse event or publication of a potentially flawed/highly disputable meta-analysis. Continual postmarketing monitoring, through observational registries and signal analysis, is the radar that can give the company an early alert on potential safety issues and enable the company to develop a proactive strategy where necessary. Postmarketing surveillance is integral to the issue of corporate commitment. It’s critical to establish cross-functional ownership of postmarketing research. Postmarketing research needs to be considered just as important to the product life cycle as preregistrations, launch plans, DTC, detailing, line extensions, and generic defense strategies are today. It’s the responsibility of all parties charged with managing the product, including brand management, medical affairs, outcomes, and regulatory affairs. The stage is set to conduct far more postapproval studies, and brand management, with executive support, should be elevating its strategic priority.” Perhaps one of the most challenging aspects of conducting postmarketing research is reaching an agreement at the planning stage with the various stakeholders. Dr. James Esinhart Chiltern International Nayan Nanavati Parexel The proposed changes by the FDA, if coupled with the funding that Congress may provide to the agency, will allow the FDA to better manage, better track, and better enforce product safety in the marketplace. FDA’s Postmarketing Drug-Safety Initiatives In June 2007, the Food and Drug Administration announced a new advisory committee designed to counsel the agency on how to strengthen the communication of risks and benefits of FDA-regulated products to the public. The June announcement builds on an outline released by the FDA in January 2007 that reinforced the agency’s commitment to the safety of drugs and other medical products. The FDA report details a series of initial steps that aim to ensure the FDA’s safety programs are the best possible. The FDA plans to strengthen the drug-safety system with a number of actions in support of three key efforts: Strengthening the science that supports the FDA’s medical product safety system at every stage of the product life cycle from premarket testing and development through postmarket surveillance and risk management. FDA initiatives include developing new scientific approaches to detecting, understanding, predicting, and preventing adverse events, developing and incorporating new quantitative tools in the assessment of benefit and risk, and conducting a pilot program to review the safety profiles of certain newly approved drugs on a regularly scheduled basis. . Improving communication and information flow among all stakeholders engaged in promoting the safe use of medical products. FDA initiatives include establishing an advisory committee. Improving operations and management to ensure implementation of the review, analysis, consultation, and communication processes needed to strengthen the U.S. drug-safety system. FDA initiatives include engaging external management consultants to help the Center for Drug Evaluation and Research (CDER) develop a comprehensive strategy for improving CDER’s organizational culture, and making specific organizational and management changes to increase communications among review and safety staff. As part of reauthorization of the Prescription Drug User Fee program, the FDA in January 2007 proposed recommendations that would broaden and upgrade the agency’s drug-safety program, as well as increase resources for review of television drug advertising and facilitate more efficient development of safe and effective new medications for the American public. As part of the reauthorization of the program, annual user fee collections will be increased to $392.8 million, an $87.4 million increase over the current base line. The biggest recommended increase, $29.3 million, would provide a major boost for FDA activities to ensure the safety of medications after they are on the market. The increased funds would be available for FDA drug-safety activities for marketed medications as long as they remain on the market and would increase the FDA’s drug-safety capacity for surveillance, including hiring an additional 82 employees to perform postmarket safety work. To that end, the FDA also recommends elimination of a statutory provision under which PDUFA fees may be used to assess safety issues only during the first three years after the product’s approval. The agency also would use the added resources to adopt new scientific approaches and improve the utility of existing tools for the detection and prevention of adverse events, for example, obtaining access to the best available databases to better analyze drug-safety signals. Source: Food and Drug Administration, Rockville, Md. For more information, visit fda.gov. Dr. Gregory Page Deloitte & Touche I have a concern that as we focus more on safety, we may start to whittle away at the ability of drug companies to innovate and introduce new drugs. Dr. Gerald Faich United BioSource Corp. There already was a movement toward postmarketing commitments and greater accountability. The Congressional Bills are an effort to further empower the FDA. Dr. Paul Seligman CDER Accurate, important, timely information, particularly after a product has been approved, is critical to physicians and healthcare providers who are making decisions about how to use medical products. James D. Esinhart, Ph.D. Executive VP, Biometrics and Late Phase, Chiltern International, Wilmington, N.C.; Chiltern is a global contract research organization with experience running international Phase I to Phase IV clinical trials. For more information, visit chiltern.com. Gerald A. Faich, M.D. Senior VP, Epidemiology and Risk Management, United BioSource Corp. (UBC), Bethesda, Md.; UBC is a global pharmaceutical services organization that generates real-world data to support the development and commercialization of medical products. For more information, visit unitedbiosource.com. Dr. Faich was formerly the head of the Office of Epidemiology and Statistics at the FDA. Joseph Feczko, M.D. Chief Medical Officer, Pfizer Inc., New York; Pfizer is committed to helping people improve their health by discovering and developing medicines. For more information, visit pfizer.com. Nayan Nanavati. VP, Americas, Peri-approval Clinical Excellence, Parexel International, Waltham, Mass.; Parexel is a global bio/pharmaceutical services organization that helps clients expedite time-to-market through development and launch services. For more information, visit parexel.com. Gregory V. Page, Ph.D. FDA Practice Leader, Deloitte & Touche USA LLP, New York; Deloitte & Touche USA, provides audit, tax, consulting, and financial advisory services. For more information, visit deloitte.com. Paul J. Seligman, M.D., M.P.H. Associate Director for Safety Policy and Communication, Food and Drug Administration’s Center for Drug Evaluation and Research (CDER), Rockville, Md.; The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices. For more information, visit fda.gov. Patricia A. Steigerwald, MS, RN. VP, Global Late Phase, Kendle, Cincinnati; Kendle is a global clinical research organization and is the fourth-largest provider of Phase II to Phase IV clinical development services worldwide. For more information, visit kendle.com. Jeffrey J. Stoddard, M.D. VP of Medical and Scientific Affairs, Risk Management and Postmarketing Programs, Covance Inc., Princeton, N.J.; Covance is a comprehensive drug development services company. For more information, visit covance.com. September 2007