With the new year upon us, this column would like to to look back at the past one to review some of the important trends. In fact, the past year was a tipping point in the adoption of electronic technology in clinical trials. The industry has been on an accelerated path of adoption of electronic data capture (EDC) for several years, but I believe that we will look back on 2007 as the year in which the most significant changes in attitudes and adoption occurred. 

 Paul Bleicher MD, PhD, is the founder and chairman of Phase Forward, 880 Winter Street, Waltham, MA 02451, (888) 703-1122, paul.bleicher@phaseforward.com, www.phaseforward.com. He is a member of the Applied Clinical Trials Editorial Advisory Board. 

But rather than focus on the recent past or near term, I would like to paint a picture of clinical development as it might be at some distant future point, enabled by technology and fashioned by a variety of current and future pressures. I know some of you will tell me that I wrote a column back in October on 

 that discussed the impossibility of prediction. I freely admit that I am not a futurologist and I do not expect this world to ever come about just as I describe it in the following paragraphs. In fact, these ideas are somewhat of a 

: an extreme extension that would likely be limited by the slow pace in pharma and other factors. The future we all will likely experience will probably be much closer to the present than what I am about to describe. 

The process of drug development and drug approval is under pressure from a variety of different and sometimes contradictory forces. The forces of change that are most relevant to this discussion are drug safety, access to new medicines, and the costs of developing new medicines. The one with the most potential to create substantial change in the approval process is drug safety. 

We are currently in a cycle where concerns over public safety are at the forefront of public and regulatory discussion. In the United States, several major pharmaceutical companies have been under attack financially for safety issues in widely prescribed medicines. The public is not sufficiently educated in the meaning of risk and benefit in prescription drugs to understand safety issues in perspective and demands safer drugs through lawsuits and legislation. 

Unfortunately, it is quite evident that the clinical trial process today is insufficient to identify, characterize, and calculate all of the safety issues in a new medication. The number of patients studied in a typical NDA is too few to identify serious adverse experiences, let alone demonstrate whether they are statistically associated with the drug. In addition, reliance on spontaneous and literature reporting of adverse experiences is flawed and not adequate alone for safety surveillance. The current trend is to examine such safety issues, and even risk/benefit considerations, through careful monitoring of patients postapproval through longitudinal analyses and registries. 

On the completely opposite end of the spectrum, the public also consistently demands and hopes for the development of new, life-saving drugs for serious conditions. These demands are intensified as new health threats emerge. Of course, anyone reading this column is well aware of the tremendous costs for identifying and testing a new therapeutic agent. This is compounded by the trend to narrower indications and more "personalized" medicines. 

Meanwhile, on the technology front, in parallel with the emergence of EDC, we are witnessing a similar adoption of technologies for the delivery and monitoring of medical care. However, the adoption curve may well be different for such technologies, as the economic pressures and value achieved by these technologies aren't necessarily apparent to those who might pay for them. The technologies that are most relevant to my argument are universal access to the Internet and cell phones, electronic health records (EHR), and personalized home monitoring. 

Universal access to the Internet is arriving rapidly in the developed world. While not every family has a computer in their home, most have free access through public libraries, at least in the United States. This access will make many things possible, including the monitoring of individual patient experiences with drug therapies. 

The emergence of EHRs is already complete in some countries, where virtually 100% of patient encounters are recorded electronically. However, in the United States, estimates range in the 20% to 25% range and are increasing slowly. The potential for patient encounter data entered into EHR systems is enormous. Such data can be used to look at longitudinal physician-entered data on drug safety and efficacy without requiring specific and separate entry into registry databases. Unfortunately, even established EHR systems often are set up for scanned, faxed or blocks of textual data entry that prevents efficient use of the data for such purposes without substantial intervention. However, changes in health care and a focus on cost effectiveness and outcomes by payors may make it more likely for such systems to be developed and/or installed with the intention to extract and examine longitudinal data. 

Finally, the availability of personal home monitoring technologies is increasing. These include patient/provider Web-based communications, ambulatory blood pressure, glucose, peak respiratory flow monitoring, and many other emerging technologies. Along with standardized tests such as home pregnancy and home coagulation tests, there are companies developing a variety of assays for home use, and it is conceivable that even pharmacokinetic sampling could be performed in the future through home devices. 

As the airport poster (for Accenture, I believe) says, "This is where it gets interesting." Given a highly creative and rational regulatory environment, one can speculate on a different model for drug approval than exists today. Fanciful as it is, you will see that the model addresses the pressures previously outlined and depends on the technologies mentioned. So, let me describe for you how technology can enable a very different process for drug approvals. 

First, there are many existing and developing preclinical, in silico technologies and databases that allow for more effective screening and analysis of drug candidates for known, likely toxicities and safety issues. While these are in their infancy, it is easy to imagine a time when companies will have a substantial amount of information and some confidence about the safety issues to monitor/address in clinical development. Further, Phase 0 clinical trials will also provide information on ADME and tissue distribution that will compliment this information. However, it is difficult to foresee much of a change in the need for Phase I clinical trials. 

In this future state, I suggest that drugs might be approved based upon clinical trials that are closer to Phase II in style than Phase III. Initially, this could be used for approval of urgently needed therapies and would only be applicable for some types of drugs. These clinical trials would enroll patients from a more narrowly defined patient population than a typical Phase III, so that variance is kept to a minimum. The endpoints of the clinical trials would be based upon (also dependent on the therapy and the indication) ambulatory endpoints and patient-reported outcomes. For example, rather than measuring peak flow or blood pressure as endpoints at a three month outcome visit, these could be measured frequently or continuously by the patient using home-based devices and communicated via the Internet to a central server. In addition, it might even be possible to correlate this information with drug blood levels, obtained through home-based blood sampling. Certainly, the use of ePRO technologies could link the data, at the moment it was collected, to patient outcome data. 

The statistical analysis tools for comparing continuously monitored data exist but might need to be extended, and regulatory reviewers would need to accept such endpoints as a basis for approval. The availability of such data from ambulatory patients, along with adapted statistical techniques, would allow the determination of clinically meaningful, statistically-significant endpoints (for effective drugs, that is) with far fewer patients than would be needed for standard Phase III clinical trials. Potentially, it may be possible to correlate some endpoints in these patients directly with ambulatory pharmacokinetic measurement, to examine pharmacokinetic/pharmacodynamic correlations in ambulatory patients instead of Phase I subjects. In addition, safety parameters could be followed much more closely in these patients, and again possibly correlated with drug levels. 

The result of these trials might be a greatly accelerated approval, shaving years off of a clinical development plan of today with far fewer patients tested. This would get much needed drugs into the hands of clinicians and patients earlier, and would likely be able to better pinpoint the subset of patients who benefit from the drug. The earlier and faster approval would reduce costs of development, and mitigate the downside of developing drugs for smaller patient populations. 

The obvious response to this vision, from the traditional perspective, is that the drug would not have been tested in broader patient populations and physician settings, and that sufficient data would not have been achieved to ensure safety. Both of these issues can be addressed in the postapproval phase, as discussed in the next section. The safety issue is an interesting one. Certainly, recent history suggests that clinical trials are often insufficient for identifying the safety issues that arise from real-world use after approval. The difference between monitoring 700 and 2000 patients for unusual and rare adverse experiences is certainly real, but both dwarf in comparison to data collection from hundreds of thousands or millions of patients. 

Approval on the basis of smaller numbers of patients in Phase II is only acceptable if large numbers of patients can be routinely followed and analyzed in "real time" after approval. Thus, patients using drugs that are approved using this route would be closely followed through registries, EHR data, cell phone, and Web-based instruments for patient-reported outcome data collection and other longitudinal data sources which would be designed to collect and structure data in standardized formats for such analysis. Mechanisms for centralizing the data on regular basis (likely daily or weekly) and a requirement to continuously monitor and report on the data using data mining and data visualization tools would allow for the study of the efficacy, safety, and cost-effectiveness of the drugs in actual use, rather than the artificial setting of a clinical trial. 

Few would question that the data so obtained would be more clinically relevant than that obtained from even Phase III clinical trials. Such data could be automatically collected from very large numbers of patients, allowing for identification and study of associations with rare adverse experiences. Although the data would not be as tidy as that obtained in a clinical trial, the quantity of important data would permit proper analysis for conclusions about safety, efficacy, and cost considerations. 

The obstacles to changing drug development to allow for this type of accelerated approval/monitoring process are very significant, but the tide seems to be slowly moving in this general direction. In addition, there are other logistical issues around patient privacy that would need to be overcome. 

The one gating factor in this is the adoption and use of technologies that would allow immediate access to trial, patient experience, and longitudinal data. As an industry, we have made significant progress toward the first two of these (as mentioned in the opening paragraph), and there are many pilots underway on the latter. Nevertheless, the vision I have put forward would be entirely dependent on extensive and standardized adoption of technologies across the health care community, which most believe is many years away. Until then, it is likely we will continue depend on the tried and true method of drug approval and safety assessment. 

Articles

Technology Viewpoint

Peek into a future where drugs are approved faster and R&D is less costly thanks to technology.

How Technology Could Change Drug Approvals

Recently, there have been a number of industry articles and news pieces focusing on the growth of the clinical research market in India—specifically, the growth of CROs. What these articles fail to capture are a number of important points regarding the relevance and role of Site Management Organizations (SMOs) in helping the country deal with this rapid growth and ensuring that clinical research is being conducted following ICH-GCP and India-GCP standards. This is especially important in emerging markets such as India, where there are many investigators conducting clinical trials for the first time. 

 Dan McDonald Vice President Business Development Excel Life Sciences 

The emergence of SMOs in India has helped to alleviate this concern by assisting investigators with day-to-day study conduct activities, ensuring that investigators are following the protocol, interacting with ethics committees, and helping to provide high-quality data from sites. In fact, the vast majority of trial data that has been accepted by the FDA for Indian trials has come from studies involving SMOs. 

There is also deepening concern among regulatory bodies and sponsors related to hybrid companies that offer both CRO and SMO services in India, especially site monitoring services. These service offerings must remain distinct for several obvious reasons, the most important being that a single company cannot objectively monitor the performance of its own sites and coordinators when it has a stake in the outcome of the study. All of these factors help explain why the distinct SMO model is necessary, compelling, and thriving in India, despite its failures in other, more developed clinical research markets. 

Outside of assisting the young Indian market with conducting regulatory and ethics compliant research, the model is proliferating for a number of other reasons. "The role of the SMO in helping to develop markets is a very important one," says Steve Hussey, managing director, PRTM Management Consultants (India) Pvt. Ltd. "In Japan, many of the improvements at the site level over the past several years can be attributed to SMOs. Specifically, enrollment problems cited by almost every global pharma relating to clinical trials have virtually disappeared." 

Compared to the pool of highly qualified physicians, the number of ICH-GCP trained investigators is very low—no more than 800 by most estimates. The SMO model helps to alleviate this issue, with some of the top dedicated SMOs offering GCP training for investigators as part of their standard offering before getting physicians involved in a study. 

The GCP issue is also alleviated through the placement of a dedicated, highly trained, and experienced clinical research coordinator at each investigative site to ensure that critical study conduct activities are carried out efficiently and effectively—taking the burden off very busy investigators. Without the support of a coordinator, many physicians do not have the bandwidth to take on clinical research. 

"Clinicians in India are extremely busy and usually cannot afford to take sufficient time off to take care of all aspects of clinical trials," says Dr. Kannan M. Narayana, chief operating officer, Narayana Nethralaya Eye Hospital, Bangladore, and an investigator on a current study involving an SMO. "A site management organization is not only a necessity for busy clinicians but also ensures quality data management." 

With the emergence of SMOs in India, clinical research sponsors that have had poor experiences contracting out investigative sites now have an organization to partner with that cannot only help them select qualified institutions and investigators for clinical trials but can also play a direct role in study conduct to help ensure a site's success. 

A Closing Thought

Dan McDonald, vice president of business development for Excel Life Sciences, assesses the role of Site Management Organizations (SMOs) in India and discusses their contributions, which include GCP training and assistance for investigators.

India Benefits from SMO Presence

EDC 4.1 System Goes Through Paces; Document Management Announced

(Wayne, PA) recently completed its 140-point user requirements validation of its ViewPoint FUSE EDC 4.1 platform. These requirements were related to 21 CFR Part 11 compliance; management of sites, subjects, and case books; data entry and review processes; edit checks; and manual- and system-generated queries.  

The company also announced its ViewPoint for Document Management, a solution combining document management, authoring templates, document standards, and expert guidance. It is offered in two models: a traditional install/implementation and a new hosted model that eliminates installation, hardware, and validation costs in favor of a direct connection to Octagon resources.  

Octagon Research Solutions, (610) 535-6500, 

eShowcase

eShowcase: Company Introduces and Validated Products

Clinical research and pharmacovigilance (PV)

  have come a long way. Many things have changed since 120 BC, when Mithridates VI "trialed" his concoctions on convicted criminals.

  But it was more than 2000 years later that the thalidomide disaster finally alerted the world that the safety of medicines is not a given. It was indeed thalidomide that triggered a wave of governmental and regulatory activities in the 1960s, which defined the principles of modern clinical research and pharmacovigilance. 

In principle, even in light of the ever-increasing regulatory activity in the field of drug safety and risk management, three key issues dominate the current discussion on drug safety:  

Risk Management—now including risk management plans

The establishment and continuous monitoring of the benefit–risk relationship.

A truly integrated approach to pharmacovigilance and risk management—that delivers not only results but controls the overall risk management perception—does not widely exist. This is particularly challenging for small and mid-size startup R&D companies, for which the absence of such solutions can easily stall the success of development pipelines and business models. 

Safety and risk management systems aligned with company strategy that are integrated into business processes and based on a broadly managed and visible safety culture

One of the reasons for this can be seen by looking at the recent history of R&D. Clinical research has always centered on human pharmacology, therapeutic exploration, and therapeutic confirmation, as demonstrated by the traditional Phase I to III clinical development. Particularly, Phase III aims to prove efficacy and safety and produce safety data on hundreds or thousands of subjects. But there was a functional difference: Serious adverse event collection and regulatory reporting—a long standing part of clinical research—was performed by drug safety or pharmacovigilance departments, whereas the collection of nonserious adverse events was the responsibility of clinical development teams. The safety database and clinical database were held by different groups. 

This technical fact alone underlines the traditional divide that can still be observed in most companies. On one side is the clinical development group, which is on the forefront of medical development and frequently involves internationally accepted experts, with high visibility within the company. In the eyes of business management, the clinical research department was ultimately responsible for finding the blockbusters of tomorrow. On the other side is the safety department—compliance driven and mainly the keeper of timelines and completeness metrics (considered a cost center rather than a value adding activity). Two departments working on the same product, each with very distinct objectives and deliverables. The exchange of technical drug safety competence and information, residing in the drug safety group, was frequently not available to clinical teams, and vice versa. Worse, it was not deemed necessary. 

Ownership for the overall development (i.e., efficacy and safety) remain ed with the clinical team. Biased toward therapeutic use, the acceptance of risk was secondary, risk acknowledgement difficult, and risk communication nearly impossible. In fact, until recently, talking about product risk, at least in public, was unthinkable. Even in internal discussions, risk analysis and risk management either did not take place or were only subject to discussions behind closed doors. 

From the perspective of R&D companies, a number of stakeholders exist that will eventually determine the success of any development portfolio. Broadly, these stakeholders can be categorized into internal and external stakeholders [for an extensive table online, visit 

Internal stakeholders include all parts of the research companies that are affected by the success or nonsuccess of the R&D activities. They are not limited to the clinical department, and also include drug safety, regulatory, medical, finance, legal, human resources, and even sales and marketing—and of course, the owner of the company, which today normally means investors and the global financial community. External stakeholders include patients and health care providers, regulatory and government agencies, professional organizations, and policy makers, as well as the media, legal firms, pharmacies, and other drug retailers. 

Internal and external stakeholders all have one thing in common: They have interest in the investigational product, albeit for differing reasons. Whereas patients are looking for a cure for their diseases, health authorities may be looking to fulfill their public role to minimize public health risks. Legal firms may be looking out for new opportunities to increase revenue, and the media is after new headlines. Within the R&D company, it's a similar picture. The drug safety department may have different objectives and deliverables than the clinical department, and the marketing or medical group may follow business objectives that are different from other groups'. 

There is a wide variety of how different functions communicate within companies of different sizes and geography. Top 10 companies appear to be more aware of the advantages of integration, although true implementation and alignment is not frequently found. This internal misalignment is matched by a perceived or actual conflict of interest between the pharmaceutical industry, regulatory bodies, patient groups, and health professionals, and has developed into a major problem for pharmacovigilance

  and return on investment. And this situation is at least partially to blame for why we face more stringent regulations: Governments and the public don't trust pharmaceutical and biotechnological companies to get risk management right. Internal disconnect and competition leads to external loss of credibility. And risk perception becomes more important than the actual risk. 

Failure, withdrawals, and new regulations

Many international pharmaceutical companies suffered at least one product recall in recent years. The last decade also saw a significant number of high-profile brands publicly struggling with safety concerns, alerting lawmakers in the United States to ask for stricter laws and regulations.

  Many smaller and startup biopharmaceutical companies are getting increasingly concerned about how to reduce the risk of their portfolios and where to find the support and expertise to develop an appropriate safety and risk management strategy. 

All these public safety events fuel civic discussions, alert politicians and public health officials, and motivate law firms to file for class actions. More importantly, they confirm the old public perception that biopharmaceutical companies want to hide information on the risks of their products. 

Clearly, many existing clinical development and drug safety systems were not designed proactively, wisely or to manage risks as required by the comprehensive list of regulations for drug safety and risk management. These new regulations mean that the compliance paradigm does not control the situation—and more needs to be done. Compliance per se is a necessary prerequisite, but it is not suitable to demonstrate the safety of products and manage risks appropriately. Only a safety and risk management system can do this. 

Increased legislation and public skepticism suddenly threaten the return on investment for researching companies. Shares may drop significantly because of safety concerns, and the perception or suspicion of risk could lead to a less favorable financial risk assessment. In financial management, the higher the risk, the less money companies have to invest and the less money for R&D. To escape this vicious cycle, R&D companies are faced with the following challenges:  

Risk limitation through the introduction of an integrated, company wide safety and risk management strategy and infrastructure

Elimination of the traditional silo culture between R&D, safety, and other stakeholders

Integration of clinical development operations into the pharmacovigilance value chain

Establishment of risk management and pharmacovigilance as value-adding processes within clinical development

Improve time to market through a systems approach, aligning people, process, technology, and governance structure

Integration of risk communication and public risk perception as part of risk management

Management of change = change management (role of professional managers).

The industry is waking up to the fact that successful risk management and pharmacovigilance is a system output rather than the deliverable of a department or group. As a direct or indirect consequence of the changes in the regulatory environment, there is an increasing number of guidance coming from experts and regulatory agencies alike to describe their vision of future pharmacovigilance and R&D systems.

There is little doubt about the fact that the purpose of pharmacovigilance is to promote the safe clinical use of medicines, prevent adverse drug reactions, and, thus, protect public health.

  Any model will—on a technical level—need to include best evidence and robust scientific decision making, supported by effective tools, to deliver protection to public health, scientific development, and audits.

  The implications of this rather technical aspect support the call for integrated systems. 

The fact that recent risk management regulations require companies to shift risk management activities to earlier phases of clinical development does not automatically mean that risk is actually being managed in the best possible fashion. In integrated systems, integration of risk management and the change of paradigms toward proactive risk and safety management are necessary. This is opening the discussion to a wider field of stakeholders, such as the public and regulators. 

On the company level, and more in line with the development of a safety vision, are calls for a company-wide policy of precaution

  and acceptance of the "precautionary principle" for risk management to avoid arbitrary and unpredictable decision making.

  Implicit in such a system is the requirement to promote risk communication and the appropriate transparency of the entire lifecycle of a product. 

In recognizing that lifecycle drug safety and risk management are rapidly moving beyond the core competencies of R&D and drug safety departments, it becomes evident that frequent marketing and other means of communication influence the overall risk–benefit balance, or at least its perception, of a product. Henceforth, marketing and marketing strategy become integral parts of risk management.

Also, the question needs to be asked how to acquire and compile safety information and where to get this information from. One possible approach could be the concept of Safety Evaluation Plans as a medium to assemble and communicate information on safety concerns from a wide range of sources during clinical development.

  Such plans include a structured approach to the definition of a potential safety concern, its evaluation (including risk assessment), and potential implications. 

Although all of these approaches add important value to the design of R&D programs, they miss one important point: how companies of different sizes and geographies can deliver integrated lifecycle risk management as an outcome of all their internal systems, rather than of one or two departments. 

As with an orchestra, it is important to identify the conductor, or governance structure. Very clearly, the skills required for the development of an integrated pharmacovigilance and risk management system go well beyond the traditional remit of R&D and pharmacovigilance departments: they are C-suite responsibilities. The person responsible for pharmacovigilance and risk management should sit in the boardroom. 

Once leadership is established, the question of how a safety and risk management culture can be created and maintained and how to manage this change needs to be addressed. The required skill sets are clearly no longer limited to medical and scientific skills. Higher level management skills are required to visibly lead such an effort.

  Finding the right set of expertise and competencies is critical in making the transformation a success. For smaller companies, the task is much more complicated than just appointing a pharmacovigilance manager. 

Systems development requires the integration of people, processes, and technology under strategy governance in order to be aligned with business strategy. The strategic aspect of developing a pharmacovigilance system means that such a venture needs to be future oriented from the very beginning. Truly proactive planning of an entire lifecycle pharmacovigilance system requires those involved to answer one important question: What needs to be done to get my product to the market on time and in five or eight years? The here and now is less important than the tomorrow, particularly since it will be likely that future competition will not only take place on the basis of efficacy, but also on safety and risk. 

A fully integrated approach to drug safety and risk management as corporate commitment leads to competitive advantages through the creation of core competencies. This model is based on the definition of a pharmacovigilance value chain, which sees a company-wide safety culture developing on the back of a vision and includes all stakeholders (see Figure 1). 

Figure 1. In this model, which integrates all internal stakeholders, risk management strategy is an integral part of pharmacovigilance. To create such a value chain, companies must be willing to make changes.  

This model accounts for the fact that most companies will not be in the position to build an integrated pharmacovigilance and risk management system from scratch. It allows companies to perform a thorough analysis of already existing systems and core competencies. This analysis, which integrates all internal stakeholders of pharmacovigilance, is an important tool to develop an appropriate strategy. Integrated into the value chain model is risk management strategy as an integral part of lifecycle pharmacovigilance. To support safety and risk communication, it is important to harmonize language (see sidebar). 

Feature Article

Truly integrated risk management requires breaking down silos and strong business leadership from the top.

Pharmacovigilance: A Company-Wide Challenge

IIR's Clinical Trials Congress
  February 25­27, 2008
  Loews Royal Pacific Resort, Orlando, FL



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New Version Extends Data Cleaning and Query Functions

 (Waltham, MA) announces significant updates to its Web Submission Data Manager, WebSDM 2.6. WebSDM 2.6 integrates with the company's InForm Integrated Trial Management EDC product Version 4.6 and other database applications, and allows InForm 4.6 users to examine source records directly in the original context to understand data cleaning status and raise queries when needed at an earlier stage. This allows for detection of anomalies and trends for safety analysis.  

WebSDM 2.6 also checks data for CDISC SDTM conformance, provides Web services API for automated data loading and improved integration with external data repositories such as Janus, and is validated for use on 64-bit platforms and Oracle Database 10g.  

eShowcase: Web Submission Data Manager Updated

Twenty years of increased assignments and declining budgets have changed the Food and Drug Administration from the world's gold standard for drug regulation into an agency with "serious scientific deficiencies" that cannot meet its regulatory responsibilities, according to the agency's advisory Science Board. In a scathing analysis issued last December (2007), the panel described how FDA "will flounder and ultimately fail" without strong scientific research programs and updated information infrastructure. "While the world of drug discovery and development has undergone revolutionary change—shifting from cellular to molecular and gene-based approaches—FDA's evaluation methods have remained largely unchanged over the last half century," according to "FDA Science and Mission at Risk" [http://

www.fda.gov/OHRMS/dockets/AC/07/briefing/2007-4329b_02_01_FDA%20Report%20on%20Science%20and%20Technology.pdf

The main culprit is inadequate funding. FDA lacks the staff and resources to support regulatory functions and keep up with scientific advances in systems biology, nanotechnology, medical imaging, robotics, cell-based products, regenerative medicine, and combination products, explained Gail Cassell, Eli Lilly vice president and chair of the Science Board subcommittee issuing the report. FDA needs the expertise to understand these developments and their role in ensuring the safety of medical products and the nation's food supply. 

Fast-expanding user fees have made up for some of FDA's funding deficit, but increased reliance on industry payments, which will total $522 million in 2008—almost one fourth of FDA's total budget—has created inequities within the agency. This is particularly true for the Center for Drug Evaluation and Research (CDER), where almost half of its $682.8 million 2008 budget comes from user fees. An analysis by panel member and prominent attorney Peter Barton Hutt reveals that any FDA budget increases over the past 20 years have been lost to inflation. The agency has gained only 700 appropriated staffers during this period, even though its work was expanded by hundreds of statutes, executive orders, and other mandates. 

Failure to Launch: New Drug Approvals Decline 

A key FDA need is an information technology system able to process and integrate vast amounts of scientific information. The FDA IT infrastructure is "obsolete, unstable, and lacks sufficient controls to ensure continuity of operations," reported Dale Nordenberg of PriceWaterhouseCoopers, who served on the panel. FDA spends about $200 million on IT, he explained, but requires at least another $200 million to be able to assess reams of clinical trial data and to track thousands of manufacturing and research sites around the world. 

Without adequate staff and IT resources, FDA cannot implement cutting-edge approaches to modeling, risk assessment, and data analysis so important to fulfilling its regulatory mission, Cassell noted. The panel recommends naming a chief scientific officer at FDA to oversee expanded scientific programs and extramural collaborations, including a new Incubator for Innovation in Regulatory and Information Science (IIRIS) to support innovation across all FDA-regulated industries. 

This and other specifics on how scientific research supports FDA assessment of clinical trials, manufacturing facilities, and product applications attracted interest on Capitol Hill. Senate Health Committee Chairman Edward Kennedy (D-MA) termed the analysis a "wake-up call" to provide FDA with the resources needed to do its job, and Rep. Henry Waxman (D-CA) urged administration leaders to tackle these problems. 

Only a few days later, though, Congress approved a long-delayed omnibus budget bill for fiscal year 2008 (began October 1, 2007) that boosted FDA's total budget to $2.2 billion—$1.7 billion without user fees. In light of heavy spending cuts across the federal government, FDA did well to receive any increase at all. But this year's budget falls far short of the $2 billion annual appropriation sought by agency advocates. 

Moreover, Congress utilizes the appropriation process to specify how FDA should spend its money and to micromanage agency policies. Most of CDER's increase is earmarked for drug safety and generic drug regulation. There is $7.5 million for FDA's Critical Path Initiative (CPI), but that is much less than initially proposed by the Senate, and about one third of it has to be disbursed to universities and nonprofits doing CPI research. 

The legislators further instruct the agency to work with pharmacy and patient groups to improve the MedGuide program, reflecting pharmacists' fears of being overwhelmed by a growing volume of patient leaflets on specific drugs. And FDA has to produce a long list of studies and reports on everything from Ketek safety to microbial resistance. The final legislation omits an earlier provision to expand drug reimportation, but still requires FDA to analyze how well it oversees foreign manufacturers of active drug ingredients. 

In an unexpected move, Congress provides an added $4 million to oversee direct-to-consumer drug advertising instead of implementing a new user fee program established by the FDA Amendments Act (FDAAA). Industry was willing to pay an extra $6.5 million in fees to support more timely and predictable assessments of drug TV commercials, but some legislators objected to the arrangement and slipped the change into the final bill. 

This reversal reflects ongoing concerns on Capitol Hill about pharmaceutical company influence on FDA policies. Congress reminds FDA in the budget bill to reduce the number of advisory committee members with conflicts-of-interest. The legislation also undermines the launch of the Reagan-Udall Foundation, which was authorized by FDAAA, by stipulating that FDA cannot use any appropriated funds to support this new organization. Rep. Rosa DeLauro (D-CT), chair of the House Appropriations subcommittee that oversees FDA, put a hold on funding the new organization for fear that it would permit drug companies to shape FDA actions related to drug safety. 

While FDA officials hope to assuage DeLauro's concerns, the rift is likely to slow down Reagan-Udall initiatives, such as helping to establish a new active surveillance system for drugs, also encouraged by FDAAA. Former FDA commissioner Mark McClellan, named chair of Reagan-Udall, is a leading advocate of using health system databases and IT systems to detect and analyze drug safety signals earlier and faster. Establishing the surveillance system is no easy undertaking and will require new data standards and collaborative efforts, tasks suitable for this public–private foundation. 

Dropping the DTC user fees is an unusual step for Congress. Legislators generally find it convenient to tap this  source of revenue to fund FDA and are proposing more new fees to bolster the agency's ability to monitor the soaring volume of food and drugs imported from overseas. In the past year, FDA faced crises involving contaminated pet food and toothpaste from China and medicines laced with diethylene glycol that took lives in developing countries. 

The FDA's field force is sorely depleted and requires added resources to inspect the growing volume of overseas manufacturers and research sites. A recent proposal is for FDA to establish permanent overseas inspection offices in both India and China. FDA signed a memoranda of agreement with China in December that encourages safety certification of exported drugs and information sharing related to inspections. 

The hope is that increased public focus on unsafe food and drug imports may prompt Congress and the Bush administration to boost FDA funding. A more likely scenario, however, is that the policymakers will instruct FDA to do more with the limited financial resources it already has. 

View from Washington

The agency's 2008 budget fails to keep up with expanding programs, added safety concerns.