Pharma's finger of blame once again points outward, never inward.


Lack of clinical trials infrastructure "may become an important bottleneck" for provision of medicines in poorer countries, warns a new pharmaceutical industry attempt to justify and defend the lack of effective action to date on medicines provision for diseases in the developing world.

A just-published study from the International Federation of Pharmaceutical Manufacturers Associations (IFPMA) called "Research and Development for Neglected Diseases: Lessons Learned and Remaining Challenges" [available at http://www.efpia.org/2_indust/IFPMAbrochnegdis2004.pdf] aims to deflect some of the criticism the drug industry has been attracting as the north-south gap in medicines provision widens.

The study is guardedly optimistic about the future: "The number of compounds in development for these diseases will increase," it claims. But one of the key gaps in delivery is likely to be an appropriate clinical trial framework.

"Neglected diseases may represent a particular challenge in terms of clinical trials, as they affect the most marginalized populations, without access to any (even most basic) healthcare facilities," says the industry publication. In a bid to focus attention on failings elsewhere than among multinational drug firms, it argues that populations often have poor literacy, creating additional difficulties for overcoming culture barriers and ensuring genuine informed consent. In addition, it points out, military conflicts in regions where neglected diseases are endemic "may have a negative impact on the discipline required to conduct valid trials." 

"In short, clinical trials infrastructure in developing countries where neglected diseases are endemic seems very limited," the study concludes. And as a consequence, different R&D projects within a new scheme for anti-malarials may soon be competing with each other not for financial resources, but for clinical trials sites in Africa, it says.In addition, IFPMA highlights the "important issue of regulatory capacities in developing countries that are needed to fully evaluate regulatory submissions." Currently, most developing countries' regulatory authorities rely on one or more developed country approval. This is an imperfect situation, IFPMA points out, since authorities such as the Food and Drug Administration or the European Medicines Evaluation Agency are obliged to apply northern risk-benefit calculations to their evaluations, and these may be inappropriate in the target countries. 

For instance, the rotavirus vaccine was withdrawn from the U.S. market in 1999, due to the observed risk of developing intus susception during the postmarketing surveillance.  This risk, while significant by U.S. standards (where very few deaths result from diarrhea), could probably be accepted in high-burden developing countries where 1.8 million children die of diarrhea every year, says IFPMA.

IFPMA doesn't offer the solutions itself, but it does offer pointers to some possible solutions. It urges "capacity building initiatives" targeting clinical trials. It says "different stakeholders need to collaborate to develop necessary infrastructure, including appropriate training of clinicians."

As it points out, some of this is already contemplated in the newly established European & Developing Countries Clinical Trials Partnership (about which this column has provided updates over the last year or so), with a focus on capacity building for HIV/AIDS, malaria, and tuberculosis trials. But as it also points out, this partnership "needs to establish effective working relationships with existing R&D organizations and also needs to be sufficiently funded to succeed. Without any doubt, an expanded initiative is needed for neglected diseases."

IFPMA insists that urgent and major efforts are required so developing countries can conduct late-stage clinical trials, have swift product registration and postapproval evaluation of medicines, and identify the best ways of applying new medicines to neglected diseases. And to deal with the authorization dilemma, "concerted action between regulatory authorities and drug companies is needed to develop innovative models for drug assessment and thus increase R&D productivity."


There is no doubt that the drug industry is not the only culprit-and maybe not even the chief culprit-in the continuing absence of effective treatments for disease in many poor countries. While a large number of the world's poorest people continue to bear a heavy but avoidable health burden, there are many other factors at play besides the availability of medicines. 

The IFPMA study particularly highlights poverty and political instability, and spells out how even the best-intentioned approaches are often frustrated by on-the-ground circumstances. It alludes to "often questionable government prioritization" in disease-ridden countries.

And it makes clear that for many diseases, the remedies already exist but are just not being deployed. "Most of [the] diseases that disproportionately affect low-income countries can be treated or prevented with easily available existing agents, such as medicines from the WHO's Essential Drugs List," it observes drily.


The study speaks glowingly of the "vast array of on-going efforts to develop and deliver new medicines" for populations in poor countries, and details many of the genuine achievements to date. It evokes "the sustained commitment" of pharmaceutical companies, "contributing significant resources and expertise and making significant new investments that focus exclusively on the health problems of poor populations."


But the industry, in its determination to paint itself in decent colors, runs the risk of provoking yet more obloquy if it is too insistent on its innocence. 

It piously-almost smugly-remarks that "important health needs of poor populations are neglected despite the availability of safe, effective, and inexpensive medical tools that if applied properly, could rid these populations of their excessive health burden." And where treatments are not available, it blames "the lack of interest among public health policy makers to invest in neglected diseases control," and the neglect of crucial new knowledge by the scientific community.

The study displays a determination to talk tough that may win it fewer friends than it needs in this debate. An underlying message that is uncomfortably close to "don't blame us, we need to make profits" repeats itself throughout the study. It insists that any discussion of "the need for novel interventions" should be carefully framed so that it does not "lead to unnecessary resource waste and create expectations that cannot be met." And in a tone redolent of a financial manager rather than a philanthropist, it urges: "Concerted efforts need to be made to streamline the development of new drugs in order to reduce the overall cost of R&D for neglected diseases."


Meanwhile, back home, it is all-change time, with a new European Commission taking over in Brussels (see the regulatory agencies update in this issue). New rules are in place for the new European drug assessment body, the Committee for Medicinal Products for Human Use (CMPH), which has replaced the former Committee for Proprietary Medicinal Products within the European Medicines Agency in London. The new committee has just published its rules of procedure-which in summary amount to the following.  

It will consist of one member appointed by each of the EU Member States for a renewable term of three years, and up to five co-opted expert members. For each scientific evaluation of a medicine, a rapporteur will be appointed from among the members of the Committee "on the basis of objective criteria," who will head an assessment team selected from among the pool of designated EU experts. But the committee itself will adopt the opinion on each particular issue.

The committee will also establish working parties and scientific advisory groups. And it may seek the services of experts in specific scientific or technical fields, particularly on clinical safety issues.

Applicants can ask to be allowed to provide oral explanations in connection with an evaluation procedure, and the committee can ask any other relevant third party for a hearing too.

For opinions where a re-examination is necessary-usually following an appeal from a company-a different rapporteur will be appointed, with "best endeavours to ensure a new examination, independent from the first opinion."

Advice will be given to applicants for marketing authorizations on the tests and trials necessary to demonstrate the quality, safety, and efficacy of their products, particularly for the development of new therapies.

The quorum required for adoption of scientific opinions or recommendations is set at two thirds of the members.  "Whenever possible," adoption is to be by consensus; if not by consensus, then by absolute majority. Divergent positions-and the names of those expressing them-are to be mentioned in the opinion.

Provision is made for urgent decisions on pharmacovigilance, serious concerns on public health, or quality defects.

No members or experts may have direct interests in the pharmaceutical industry which could affect their impartiality, and they must undertake to act in the public interest and in an independent manner, and make an annual declaration of their financial interests.			

Articles

View from Brussels

It's Not Our Fault, Says Drug Industry...Again

The Medicare drug benefit and FDA's Critical Path Initiative will push and pull new drug development.

Several important events during the past year promise to reshape the environment for developing and testing new medical products. Congress established prescription drug coverage for some 40 million Medicare beneficiaries, a vast expansion of federal support for and control of expenditures on medicines. Even in its early stages, this program is focusing public attention on prescription drug prices, marketing, utilization, and effectiveness.

At the same time, concern that increased public and private investment in biomedical research is not yielding more new applications for innovative new therapies spurred a number of regulatory initiatives designed to streamline and accelerate new drug development. 

The need for major changes in medical research and testing also was highlighted by developments that raised serious questions about the adequacy of current pre-approval testing and postapproval oversight of several widely used drugs.


The Medicare drug benefit is expected to boost prescription drug use by seniors and provide incentives to develop therapies needed by elderly patients such as arthritis, cardiovascular conditions, and Alzheimer's disease. But it also may squeeze prices and profit margins of pharmaceutical companies that sponsor research. A new payment system for oncology treatments and other therapies administered by physicians may alter incentives for R&D in these areas, while the Medicare outpatient pharmacy benefit will establish model formularies, post negotiated prices, promote treatment protocols, and track adverse events and outcomes more thoroughly-all likely to shape prescribing practices and new product utilization. These developments will require sponsors to incorporate outcomes measures into studies earlier in the development process, and may cause earlier abandonment of unpromising research. 


The Food and Drug Administration unveiled its "Critical Path" report in March to stimulate new thinking about how to convert new biomedical discoveries into safe and effective therapies more quickly and more efficiently. Former FDA commissioner Mark McClellan championed the initiative due to concerns about the lag between gains in genomic and other cutting-edge biomedical research and the development of new medicines able to improve public health. The report aims to examine and improve techniques used to evaluate the safety, efficacy, and quality of medical products by identifying obstacles and possible solutions to the high failure rate of potential new medical products during the development process. 

The Critical Path report supports more translational research at the National Institutes of Health (NIH) and other organizations, and highlights the need for new tools and strategies to improve clinical trial design. FDA is seeking ways to identify new biomarkers and surrogate endpoints linked with clinical outcomes, and exploring how pharmacogenomics (PG) and proteomics can help target responders, monitor clinical response, and measure drug effectiveness. 


A related FDA initiative aims to encourage sponsors to expand their use of genomics information to spur discovery of more individualized dosages and treatment regimens. For the past year, FDA has been working to finalize a draft guidance issued in November 2003 designed to encourage pharma companies to voluntarily share internally developed PG data with FDA. This information may help sponsors select high-response individuals for clinical trials, a strategy that promises to reduce clinical research costs, accelerate drug development, and promote appropriate and safe use of complex new treatments. Pharma companies acknowledge that they are using PG information to better understand metabolic effects of test therapies, but most companies are reluctant to submit this data to FDA. They fear it will raise questions that could delay product approval or limit its approved label. FDA's data submissions guidance would allow sponsors to send in genomic data voluntarily for analysis by a special FDA review group, separate from the established new drug review process. 

In clarifying its PG policy, FDA found that sponsors also fear that information on new biomarkers might prompt the agency to require a company to co-develop a diagnostic test in order to bring a new pharmacogenomic treatment to market. The emergence of more genomic markers that can identify high- and low-responding patients is prompting regulators to encourage the development of diagnostic tests able to determine which patients should be treated with a therapy, the appropriate dose, and risks associated with treatment. 

FDA is considering additional guidance to clarify how it should regulate diagnostics and pharmacologic interventions that may be developed by different manufacturers and traditionally are considered separate entities for regulatory, reimbursement, and clinical practice purposes. Different FDA centers regulate medical devices, drugs, and biologics, providing more need for the agency's Office of Combination Products to oversee medical products that involve multiple components. 

While some FDA staffers would like to require the use of a diagnostic for any PG therapy with an identifiable biomarker, manufacturers seek a more flexible approach to co-development that recognizes the significant differences in processes and practices for producing diagnostics as compared to drugs and biologics.


FDA also seeks to streamline research and the application review process by encouraging sponsors to submit more data electronically. The Department of Health and Human Services (HHS) intensified its push for a national electronic medical records system during this past year, starting with an effort to reach agreement on health terminology and electronic data standards. FDA is supporting the e-health initiative by proposing new systems for recording and transmitting research information. While these approaches may have long-term benefits in ensuring the accuracy of data and reducing research expenditures, the transition will be complex and costly in the short run.


The fall of 2004 was marked by a number of crises for the pharmaceutical industry and for federal regulators that raised serious questions about pre- and postapproval safety testing of new products. After months of debate, the experts decided that antidepressants may cause serious problems for young patients and warrant black box warnings. FDA subsequently required labeling changes for these products, plus MedGuides for patients to clarify the additional risks. Then, Merck had to pull Vioxx off the market due to evidence that long-term use of the COX-2 inhibitor raised the risk of cardiac events. On another front, British regulators shut down Chiron's Liverpool, UK vaccine manufacturing plant, creating a serious shortage of flu vaccine in the United States for the flu season. 

Members of Congress pointed fingers at lax FDA oversight, accusing agency officials of trying to squelch staff warnings on drug safety issues and of ignoring signs of trouble at Chiron. One response was to call for full disclosure of all clinical trial results by sponsors and FDA-including those studies that fail to demonstrate efficacy. The reluctance of sponsors to provide timely information on clinical trials enrolling subjects and to fully disclose study results drew sharp rebukes and demands for policy changes. Investigators launched probes into possible unethical manufacturer behavior, as government officials and industry leaders weighed a range of messages emerging from these events: 

 the nation's adverse event reporting and postmarketing surveillance systems are limited and slow to identify looming safety problems


 sponsors may need to provide much more safety data to bring to market treatments that patients may use for years


 DTC advertising for chronic-use drugs may encourage overmedication and unsafe practices


 the U.S. vaccine supply system is antiquated and unreliable and needs a major overhaul to prevent shortages and inequitable access


 perhaps regulators and policy makers should rethink efforts over the past decade to accelerate the drug approval process and streamline research requirements.

All these issues will be on the agenda for health and medical policy debates in coming months.


For some time now, the U.S. healthcare system has been plagued by shortages of many vaccines for children and during flu season. Observers describe the nation's vaccine supply system as "very fragile" and "unreliable," characteristics that have escalated with the departure of major pharma companies from the vaccine business. Flu vaccine shortages in 2000 and 2003 prompted the Centers for Disease Control and Prevention (CDC) to ramp up supplies this year, particularly to meet growing demand generated by the government's own campaign encouraging patients to get a shot.

A key component of CDC's plan to ensure broader access to flu vaccine involved signing up San Francisco-based Chiron to provide over 40 million doses this fall from its newly acquired Liverpool, UK plant. The plan fell apart in October, though, when British regulatory authorities suspended the license of the facility due to "issues with systems and processes" designed to ensure product quality. While the Brits stood to lose less than 20% of their annual flu vaccine supply, an amount that other manufacturers could fill, the shutdown is devastating to the United States, which had relied on Chiron for about half of its 100 million dose order. Chiron bought the facility from PowderJect Pharmaceuticals in July 2003, and spent $75 million to upgrade the facility. But the company may have been pouring money down a sinkhole.

In August of 2004, Chiron acknowledged contamination problems with actual vaccine lots, but still assured FDA that it was an isolated situation, easily remedied. In fact, just a few days before the shut-down, Chiron CEO Howard Pien told a Senate committee that it had addressed its contamination issues and would deliver flu vaccine as promised. FDA officials were awaiting a Chiron report when Britain's Medicines and Healthcare Products Regulatory Agency closed the plant for three months because its inspectors did not feel that Chiron would be able to fix its problems sufficiently to ensure product quality. 

While U.S. public health officials scrambled to find alternative supplies and to encourage prudent use of available doses, the Chiron debacle spotlighted serious problems with the U.S. vaccine supply system. Only two other manufacturers produce flu vaccine for the huge U.S. market, a situation that limits possibilities for dealing with emergencies. Several large companies have left the U.S. market because vaccine making is a difficult, low-profit business. Research and manufacturing are complex and susceptible to problems, and the United States offers the added threat of lawsuits and political interference. The Chiron crisis is sparking interest in a range of proposals to spur more flu vaccine production:

Expand government guarantees for vaccine purchase to cover unused doses that manufacturers often have to discard every year.


Provide grants and support for manufacturers adopting modern vaccine production techniques. National Institutes of Health officials are offering up to $150 million in financial incentives to encourage pharma companies to develop modern flu vaccine production technologies, such as cell-based cultures and DNA engineering. Everyone agrees that it's vital to shift away from today's old-fashioned egg-based systems that are slow and difficult to change, but that could take years. 


Expand vaccine production through regulatory and market reforms. A report from the National Vaccine Advisory Committee, which appeared in October as the flu vaccine crisis was emerging, recommends dropping price caps on vaccines for children, improving vaccine coverage by payers and insurers. It would also seek more harmonization in U.S., as well as foreign vaccine approval requirements to increase supplies in an emergency.-JW


Although pharma companies have long sought stronger liability protections for vaccines and drugs, bills to provide such protections have been stuck in Congress for years. The legislators approved Project BioShield legislation in July, but only after dropping key liability provisions. Now Senate Judiciary Committee chairman Orrin Hatch (R-Utah) and Senator Joseph Lieberman (D-Conn) are hoping to gain approval of a BioShield II bill next year that would create more incentives for industry to research and develop vaccines and treatments. 

Without liability protection and other provisions, industry's fairly lukewarm response to the BioShield program is likely to continue. HHS recently awarded $232 million in contracts to companies developing new vaccines against smallpox, plague, and tularemia, but the recipients are fairly small, and two are British. The Senate Judiciary and Health committees held a hearing on BioShield II last month to build support for tax incentives, intellectual property protections, and liability shields to spur more counter-terrorism product development. 

The bill includes protections from lawsuits in the case of adverse side effects from such cutting-edge therapies. A controversial proposal offers patent extensions on existing commercial products to manufacturers that create bioterror countermeasures. Even though Hatch and Lieberman would limit such patent gains to smaller firms, generics makers strongly oppose "wild-card" awards that could be applied to blockbuster drugs. 

Some health experts want to extend BioShield protection to companies that develop antibiotics, and similar proposals could be applied to vaccine producers in general and flu vaccine makers in particular. Politicians on both sides of the aisle support policies to end the continual shortages and to encourage more domestic vaccine production as a way to protect the nation's health against a flu pandemic or other health crisis.-JW			

View from Washington

Reimbursement and Regulation Shape Pharmaceutical Research

A technological look at yesterday and today could predict tomorrow's trends.


It seems like a good time to review the state of information technology in 2004. The goal of a review of this sort is to try to identify the early trends that will lead to important mainstream technologies in the future. I do this with some trepidation, as I have learned over the years that the passage of time is the only way to truly put events into perspective. In any given year, a few highly significant events occur that will later be viewed as the first public demonstration or milestone on the road to some new, important technology. Much of the time, these events will pass unnoticed or will seem an amusing oddity until time has passed and the technology matures. Hindsight, it is said, is 20/20.

Predictions of technology trends can also be way off target. Two examples that always spring to mind are the picture phone and the moon shuttle in "2001: A Space Odyssey." The picture phone was demonstrated and widely touted as a future technology at the 1964 New York World's Fair. In that vision, we would soon all have picture phones in our homes for our communications. Well, the breathless futurists figured out that such a thing was possible, but they never realized that most people were horrified by the thought of having to get out of their bathrobes and put on makeup just to speak on the phone. Kubrick's "2001" predicted that, by the title year, we would be able to take a commercial airline "shuttle" to the moon. At the height of the space program when this film was made, who could have predicted that our public appetite for lunar travel would abruptly wane soon after we demonstrated that we could do it?

To put 2004 into perspective, let's first look five and 10 years back and see what we might have said about 1999 and 1994. You will notice some interesting trends that develop as we progress through these 10 years. 


Notably, the Internet was 25 years old in 1994, but was probably just entering the consciousness of most people. 

 The obvious advance in technology in 1994 was the emergence of the Web browser, Mosaic, released on April 22. It was an immediate success, followed by the release of Netscape in December. The World Wide Web had been "invented" in 1991 by Tim Berners-Lee (no, not by Al Gore), and until Mosaic most of us had to use text-based tools like Lynx to awkwardly "surf" the Web. Incidentally, the term "surfing the Web" was coined in 1994 as well. The year marked the transition of the Internet from an academic and governmentoriented network to a commercial marketplace where stores could show their wares in catalogs. Also, commercial ISPs offering browser-based Web access became more common. 

People were talking about the "worms" that were a threat to the burgeoning network. Better known as viruses, these worms had been able to bring the early Internet to its knees on several occasions, first in 1988. 

 Many Internet locations weren't Web sites, but had a "gopher" menu, a hierarchical list of their content which could be searched across all gopher sites with a tool introduced in 1994, named "Veronica." Veronica was the distant predecessor of search engines like Google. 

Another important trend was already three years old-the Linux operating system was being worked on by a dedicated group of developers. The year 1994 saw the release of Linux 1.0.0. However, the mainstream entry of the Open Source movement was still four years away.

Personal organizers/handhelds had emerged with a variety of contenders, but the Apple Newton got most of the press. It was widely acclaimed because of the simplicity of its interface, and widely criticized because of difficulties with handwriting recognition. Lost in the noise was the appearance of the Palm Zoomer (1993), a predecessor of the Palm Pilot.

 If we had been paying careful attention in 1994, we would have been able to pick up a few early trends that became very important in later years. The first banner ads (for Zima and AT&T) were displayed in 1994 on hotwired.com and the year also saw the first spam email (for a law firm, offering "green card" services). Distribution of rich audio and video media was already in place by 1994, but the appearance of streaming media wasn't until 1995.

 Those who were predicting the future were looking at ubiquitous availability of high-speed connections in homes, rather than dialup. In addition, some began envisioning the development of significant Web applications which were more than just static Web sites-Web "apps," as they are called, would eventually allow users to access the full power of software programming through a Web browser interface. This revolution in computing would be almost invisible to the average user; but would turn the whole process of software sales, distribution, and pricing on its head.


There was no doubt by the beginning of 1999 that the Internet was here to stay; in fact, it was going to be the most dominant communication and collaboration media of the next decade. 

 Microsoft downplayed the importance of the Internet at first. However, in 1996 it reversed courses and entered the market with a consumer-oriented Web authoring tool, FrontPage. FrontPage allowed users to create "do it yourself" Web pages, with minimal experience or knowledge of Web page coding. They quickly followed this with the first "viable" release of Internet Explorer (IE), to compete with Netscape. Starting with a miniscule share of the market in 1996, IE was the dominant browser by 1999. 

In 1999 we would have spoken a lot about the impact of eCommerce on B2C (business to consumer) relationships. Catalog-type sales were becoming quite popular, along with the emergence of the Internet auction, now dominated by eBay. Online trading was part of the "froth" of the Internet bubble, with the emergence of companies like eTrade. Many people were doing their banking electronically by this time, paying bills online.

The MP3 file format was rapidly adopted in 1999 for the recording of music. The concept of P2P (peer-to-peer) also took off in 1999, with immense popularity of the grey zone of the Internet-MP3 file exchange between individuals. The record industry woke up to an enormous trend whereby young people were trading music files rather than buying them. Although not strictly P2P, Napster rocketed to popularity in this year, and in December was first sued by the Recording Industry Association of America.

Another major trend in 1999 was the personal digital assistant most frequently referred to as a Palm Pilot. The Newton and other devices had fallen from favor, but the Palm Pilot seemed to be everywhere in business settings. The ability to carry contacts, calendar, and even downloaded emails (which could be answered and uploaded at your convenience) provided an unstoppable, compelling value proposition. Palm also launched a wireless version in 1999, allowing users to connect to the Internet. 

The major mainstream trend in technology in 1999 was the race to fix the "Millennium Bug." The bug was planted inadvertently by computer programmers of the past who never conceived that their programs would last until the year 2000. Companies were racing to replace and/or repair legacy systems so that the entire technology infrastructure of the world didn't implode. In the end, the problem was very effectively dealt with and the arrival of the year 2000 brought very few issues, for a very brief time.

 Web services would eventually evolve into a major factor in software development, but in 1999 it was only being discussed by the cognoscenti. It would be another year before the first standards for Web services were established, and the world of Web services began to take off. The talk of the day in 1999 was network and thin client computing-a concept where individual users' computers were to be minimal machines, with no local applications. All applications were to be located on a server (either local or on the Internet) and provided on an "as needed" basis. While the concept as originally popularized hasn't succeeded on a wide scale, by 2004 the growth of sophisticated Web-based applications has transferred the "working end" of many programs from the desktop to the server itself.

The term "blog" was first used in 1999, a shortened version of the weblog that itself first appeared in 1997. The blog is a natural outgrowth of Internet bulletin boards, usenet groups, and Web pages-all merged together and supported by specialized content management software. "Bloggers" used the software to create personal diaries of their thoughts on whatever topics interested them, from baseball to politics. The year 1999 saw the introduction of the company/blogging software known as Blogger. Now owned by Google, Blogger allowed nontechnical users to create and manage weblogs. Early blogs were of interest to a rather narrow range of readers; the 2004 election cycle changed that dramatically.

 Those in the "know" had been using a variety of search engines prior to 1999-Yahoo, AltaVista, and a "meta-search" engine known as Dogpile. During the course of 1999, a new search engine was introduced-Google. The simple, elegant, and amazingly accurate interface was astounding to techies who discovered it through word of mouth. But few predicted that this powerful search engine would change the face of the Internet and enter the common vocabulary as a verb. Five years later, Google has become a hugely successful, public company that is used for just about everything-from research papers to criminal investigations to vetting blind dates. It was recently used to secure the release of a hostage in Iraq. Who knew?

The Open Source movement had been smoldering along in various forms until '98-'99. During this period, Netscape, which had failed dramatically against the Internet Explorer juggernaut, opened its source code to the public. Shortly after this, some of the major players in software, from Oracle to IBM, put their weight behind Linux, creating a very large potential market not only for the operating system itself, but for the many enterprise applications that would be developed for it. From Web servers to enterprise class databases, the open source movement was about to be embraced by business as an inexpensive and viable alternative to commercial software.

Advertising was everywhere on the Internet in 1999, with the now ubiquitous pop-ups and spam beginning to reach a critical mass. 

 By 1999, wireless local area networks were common in major corporations, and were becoming affordable and technologically accessible to the home user. It was not too difficult to predict that such technology would be widely available in five years, from university campuses to coffee shops. 

Our history is complete, and we will now turn our attention to the current year. And what a year it was.

 From the perspective of the mainstream, the Internet is still the biggest story in technology-a decade of the Web browser era and still going. Searching has become the organizational tool of choice for the Internet, given the power of the Google engine. Organized directories have all but been replaced by the organizational power of a Web-wide search. The Internet has progressed from the new and exciting (1994) to a tool of enormous potential (1999) to an indispensable part of the work and leisure life of most in the United States and many elsewhere. Email is still the most used technology, with the Web and Web browsers not far behind.  In 2004 ecommerce on the Web is old hat; Amazon and eBay are venerable institutions. 

Communication between people through technology has evolved from email through text messaging (especially in Europe and Japan) to instant messaging (IM). Work collaboration groups have begun to use IM applications for instant, informal communication. Parents keep in touch with their kids in college through IM, and IM can now follow us to our phones/messaging devices. But, the world is still divided into multiple camps since IM hasn't been standardized. AOL IM can't talk with Microsoft's version, and neither talk with Yahoo's. But don't dismay-Trillian (http://www.trillian.cc) speaks to them all and is free.

Open source has definitely made it into the mainstream in the corporate world. Linux, Apache, MySql, and Tomcat are strong open source products that provide the underlying software, operating system, and databases for many major commercial Web sites. They are fully featured, stable, high-performance, and high-quality products that have a huge support network of experienced and committed developers. There is certainly more to come in open source, especially for the most widely used applications, which have large numbers of committed developers willing to do the job. Open source doesn't arrive like manna from heaven; it is produced by the sweat and toil of an army of developers.The Palm Pilot model has been revolutionized by reliable wireless access to the Internet. While the traditional Palm device is still used, many have opted for devices that contain the Palm applications, but are integrated with a cell phone and wireless connectivity. The Blackberry device, which uses a pure keyboard data entry paradigm (as opposed to the pen-based Palm) has had a major impact in the market and is very apparent in many business settings. The Blackberry appears to have accomplished for wireless PDAs almost the same thing that the original Palm Pilot did-a simple, pleasant user interface that just plain works.

The wild and wooly days of music file sharing were tamed by specific lawsuits against major abusers (mainly students). Most of the file sharing market has converted to a legitimate market with Apple and Microsoft (and the original Napster!) leading the fray. Both have Web sites serving music for a small fee per song. The dominance of reliable, handheld devices for playing these tunes has driven this market. Interestingly, the next big thing in music appears to be wireless music players for the home. These provide streaming, stereo quality music to be played through a home stereo system from files that reside on a home computer. This is likely to evolve into a home server for media-music, videos, photographs-with wireless feeds to the appropriate home device and updates through the Internet.

The blog has made it to the mainstream in 2004, thanks to the United States presidential election. Thousands of blogs are extant on the Internet, capturing the daily thoughts and readings of a variety of pundits and thought leaders. As the Web browser did with advertising and sales, the blog has become the great democratizer of opinion. Regardless of whether a blogger is a famed, published commentator, or a virtual unknown, a blog will become popular based mostly on the opinions expressed within. During the nominating conventions leading up to the conventions, the bloggers were invited to attend and report on the convention as mainstream journalists. A turning point in the impact of the "blogosphere," as it is called, occurred when documents concerning the President's National Guard service were exposed as fraudulent by a dedicated group of otherwise uncoordinated bloggers. These Web sites were able to investigate and debunk the fraudulent documents in a matter of days, while the mainstream press lagged days to weeks behind. The result, most believe, is that the process of journalism has permanently changed. But the blog hasn't even started to reach its true power.

 Organization of information has become a critical issue, both on the Web and on the desktop. The two opposing philosophies are organization by hierarchy-the familiar tree structure of folders and subfolders, versus organization by search-the also familiar paradigm of the effective search (a la Google). On the Internet, the original dominant methodology was the highly structured and characterized hierarchy. An example is the old Yahoo Web directory, which still exists but is not nearly as popular as it once was. The Web directory required a very structured approach to "filing" and a similar approach to "retrieving" the information. 

Furthermore, it requires an astounding amount of maintenance. Finally, many Web sites just can't be adequately characterized into such a hierarchy. It is not surprising, therefore, that a highly effective search engine such as Google has all but captured the organization of information on the Web. Since Google can be updated "automatically," it is viewed by most as the fastest, most accessible method to bring order to a highly dispersed, chaotic universe of Web sites.

The battle of organization has finally reached the desktop. For the most organized among us, the folder/subfolder organizing system works quite well, but for others the filing and retrieving of documents requires more discipline than they have. While Microsoft always offered searching as part of the Windows operating system, the entire process is quite distasteful and ineffective at finding documents. Although Microsoft promises a new, powerful document search capability in a future version of its Longhorn operating system, this capability is likely three years away. In the interim, there are new and powerful alternatives. I recently wrote about LookOut, a free utility that plugs into Outlook and allows powerful searching of emails and files. Google recently introduced a desktop version of its search engine that indexes, searches, and retrieves links to files on the local computer just as it does on the Web. My verdict-the Google desktop search-is not the answer. The most powerful tool that I have found is available today-X1 (http://www.x1.com). This amazing utility indexes your emails, contacts, attachments, and files. It allows you to search instantly and view and/or launch your searched documents all within the application-regardless of whether they are Word, Excel, pdf, or PowerPoint presentations. Many who have tried this tool use it almost exclusively as the window to their computer.

One of the essential functions of business technology is to "grease the skids" for group collaboration. In the past this has meant using tools like eRoom, Lotus Notes, and other enterprise applications. This year has seen the emergence of two tools that are likely to make it into the mainstream over the next few years. One has already been mentioned-the blog. Rather than the political blogs we have already discussed, think about the "project blogs." These are group collaboration blogs where the bloggers are all members of the project team. The blog requires no technology expertise, little maintenance, and can establish an easily maintained repository of project knowledge. Most project blogs are likely to remain quite private, within the confines of an individual company. However, some may serve to involve customers as well. A good example of such a blog is one set up by the Microsoft "Longhorn" team, working on the next version of its operating system: http://www.longhornblogs.com/.

The Wiki is another group collaboration tool used by techies that is likely to enter the mainstream. The Wiki (meaning "quick" in Hawaiian) refers to a specialized type of collaborative Web site using Wiki software. These sites are maintained by a group of collaborators, and can be edited by any one of them. While a blog is a continuous "diary" of sorts, with each contribution listed above the last, the Wiki is a "finished" document that is being continuously edited. The Wiki tools allow for basic editing of the format, without the need for in-depth knowledge of Web (i.e., HTML) editing. A perfect use for the Wiki would be a collaborative document, like a requirements document or a clinical protocol. It is a completely different paradigm than the edit/review functionality in Word, but it works. Good evidence for the power of the Wiki is the Wikipedia, a huge encyclopedia put together just through the collaboration of anyone who wants to. That's right, anyone. The articles are very accurate and up to date. Give it a try with your favorite topic, http://www.wikipedia.org.

One of the secret weapons of blog readers is RSS, which stands for Really Simple Syndication. RSS consists of an XML file that lists the contents and brief summary of a Web site, typically one that is frequently updated. For example, a blog or a news Web site might have every new entry or news story added to the RSS file as it was added to the site. By using an RSS reader (e.g., http://www.sharpreader.com) anyone can follow new additions to the Web site simply by glancing at the reader, rather than actually visiting the page. Using an RSS reader, it is possible to follow dozens or even hundreds of Web sites daily with ease. Stories or entries that aren't of interest (based on the title or summary) can be easily ignored, and anything interesting is just a click away. RSS syndication is showing up everywhere nowadays, from Reuters the New York Times, and most every blog on the Internet. It is likely that RSS or similar technologies will become a very important technology in aggregating and managing many disparate sources of information. In fact, the major email and Web browser programs are recognizing this and incorporating RSS readers in future versions.

Speaking of Web browsers, it appears that the browser wars are back. As mentioned earlier, early Web browsers were almost entirely Netscape, but with the introduction of Internet Explorer, the market dominance market presence of Netscape disappeared. The release of the source code for Netscape seemed almost a death knell. Not quite. In fact, open source Netscape (aka Mozilla) continued to be worked on, and a lighter version of the Netscape browser known as Firefox has been released. It is light, fast, and has a number of excellent capabilities. The most significant advantage is tabbed browsing-the ability to have two, five, or 10 or more Web sites open "simultaneously" and to be able to flip between them. Firefox is rapidly gaining market share, although fewer than 10% of Web surfers are currently using it. One major advantage is that, for the moment, Firefox users are virtually exempt from spyware and popups. Other browsers that are also being used are Safari (aka Konquerer, from the KDE user interface for Linux), and Opera. It would not be surprising to see significant competition in this market in the future.

In addition to browser wars, the very techie types speak of a major war of "development environments." Commercial software is developed using certain computer languages, each with its own advantages and disadvantages. The most popular language for current development is Java from Sun in what is called the J2EE environment. J2EE enables rapid development of software which includes the robust tools necessary for modern programming-including access to Web services and databases. The competing development language from Microsoft is C# in a .NET environment, which provides similar tools. There are many arguments for each that are well beyond any discussion in this forum. However, the choice between these two dominant environments is something that is worth noting, even for the nontechnical.

Radio frequency identification (RFID) is one of the hot trends of the year. Using small devices that are transponders (e.g., they receive a radio frequency (RF) and subsequently transmit their own RF signal), RFID provides a way to tag and label anything. It can tag pharmaceutical packaging by the palette or by the vial, and provide key information on data of manufacture, packaging, originating plant, etc. RFID can tag people-very recently the FDA approved the implantation of a small identification device the size of a rice kernel subcutaneously. RFID is much more than bar coding, since it can be detected at a short distance, and without the direct contact of a reading device. It can provide identification information and location information. For example, RFID can be used for tracking personnel within a building. The major issue for RFID is bringing down the cost of the transponder to one consistent with inexpensive manufacturing. When that happens, you are likely to see every item you buy in a store from groceries to clothing be RFID tagged and tracked from manufacture to purchase at a retail store. The implications for pharmaceutical manufacturing and for clinical trials are significant.

 Wireless has, as would have been predicted in 1999, become available in homes, airports, hotels, and coffee shops. Going forward, we are likely to see even more extensive availability, and likely for very low cost. My home town has proposed to blanket the entire region with very inexpensive wireless Internet access. Others are looking into how to do this nationally and internationally.

The convergence of the cell phone, the personal digital assistant, and the computer will continue. Before long we will have fully functional personal computers that we can carry, use as telephones, and as PDAs.

RFID is destined to become a very important technology over the next few years.

Finally, the Linux desktop will soon achieve the usability and functionality of the alternative Windows and Macintosh desktop. Over time it is likely that Linux desktops will begin to appear at corporate workstations in increasing numbers. The stability of the platform and the very favorable cost considerations may provide an opportunity for corporations to move away from the commercial desktop environment.			

Technology Viewpoint

Tech Trends Come of Age

Following the examples of these six companies might change your organization for good.


 In keeping with this month's resource issue, the editors asked me to reflect on 2004's best practices in clinical development process, as seen in real life situations. Being somewhat of a non-believer in best practices (who's to say any practice is "best"?, and why is someone else's "best" necessarily best for you?), I did conclude that I could cite a number of "pretty good" process examples worthy of emulation. All of the following are actual examples; the company identities have been omitted to protect their competitive advantage. If we were giving Best Process Practices Awards this year, these would be the winners.


Mergers are rampant in our industry among companies large and small, and as far as most investors can tell, they run smoothly, even if they don't produce dramatic improvement in the flow of new drugs. But as anyone who has been inside a merger knows, the operational impact can be devastating, and at the very least, highly disruptive. Merger failures include poor understanding of where the strengths lie in the new organization, missing the opportunity to make real operational improvements, trying to keep people happy without regard to business effectiveness, keeping unproductive functions alive,and so on.

One company took a different approach. It decided to act swiftly to analyze strengths and weaknesses in the merged operations, and where necessary, create a new organization chart with re-articulated roles and responsibilities before any final management changes were announced. The analysis was rapid but intense, and informed with extra-company experience. Major re-assignments were made, even of line managers, and in some cases new units were formed for tasks the new company would be much in need of. Instead of the usual postmerger behavior, where a company just looks at the management players and leaves the rest up to them- often resulting in years of slow, distracting upheaval-this company sought to get as much change as possible accomplished quickly. And not change for change's sake, but change that was incisive and potentially transforming. An excellent approach to exploit the operational opportunity mergers present.


We have written before how critical it is to govern change effectively-that there must be empowered leadership, with money and executive backing, and an infrastructure to handle the myriad of tasks necessary to make process improvement successful. Too often in clinical development, we retreat to leaderless teams or matrixed relationships; major change is cast as an "initiative," which leaves individuals and managers free to choose whether they will commit. And without resources, both human and monetary, even strong visionaries cannot succeed.

A large pharma introducing a major change in clinical development made a significant investment in change governance this year. It wanted to move quickly but knew this change was mission-critical with high stakes. The company created a new department, which would operate globally to manage this multiyear process transition. It is a permanent unit, with permanent members formally transferred in. Former line operations staff are now fulltime change agents. Top executives are fully informed and committed to its success. The department is fully budgeted and is resourcing ahead of the curve of need, instead of behind-in itself a major accomplishment at most companies. The company has sought to staff all the roles necessary for change management, from study team mentors to investigative site trainers, and expects to achieve successful, compliant process change in much less time than most of its big pharma peers. The investment in governance is paying off.

Learning from mistakes, sincerely and concretely


Many clinical development groups routinely talk about "lessons learned." They properly seek to understand what went right or wrong with a project or particular trial, so they can avoid repeating past mistakes and remember to do again what they did right. 

Unfortunately, such efforts are usually little more than one long meeting, a flipchart pad full of observations, and a bunch of action items that individuals are supposed to remember for next time. Too often, the "learning" dies on the spot. There is no formal means of documenting the discussion, no one keeping track of actions taken, and no protection from that learning just walking out the door in the head of a departing employee. Worse, the learning is often incomplete: messengers of bad news are afraid of being shot, or the attempt to seek information may not be cast widely enough. Equally common is that the lessons are articulated too vaguely, in words and opinions too familiar to be truly heard or acted upon.

One biopharma with many lessons from a just-concluded pivotal trial decided that learning as usual was not enough. Instead, it used a formal exercise designed to comprehensively analyze and document what it had learned about this trial's conduct. The examiners looked for root causes of problems they encountered, which enabled them to identify broad but meaningful themes whose improvement will impact future trial conduct. These root causes are actionable, not theoretical, and provide a foundation for a diverse set of clinical operations process improvement steps.


We have written many times that measuring our performance can be so useful to companies understanding where and how to devote process change energies. As we have described, those companies who get "metrics religion" often go into overdrive and end up with a vast array of data, and pages of reports, which managers ignore and staff resent. Another flaw in most companies' metrics programs is a focus only on time intervals (last patient visit to database lock, for example), which are determined by too many contributing variables to derive correct conclusions.

An international biopharma has demonstrated that in one area of its operation, clinical data management, it can apply metrics for resource planning, performance monitoring, and technology assessment without falling into either of these traps. By focusing on the "vital few" metrics which are both reasonable to collect and have operational significance to know, it has been able to minimize the practical burden of performance data collection while increasing the usefulness of the results. As importantly, it is focusing on the units of work which best describe operations, rather than abstract time intervals. Using units of work translates much more accurately into management decision-making.

Knowing it's never too soon for compliance


Emerging biopharmas who are just beginning to see their first drug candidate approach Phase III usually continue the pattern of operations which got them there: use a lot of CROs, focus on the science, and ignore clinical development or postmarketing infrastructure. They follow the same philosophy they followed through discovery: I'll buy that next piece of equipment or hire that next person I need the day I need it and not a moment sooner. That can work in discovery, but having the organizational infrastructure for a successful submission and postapproval support is not something one can buy in a moment-it takes time, anticipation, skill, and practice.

Just such an emerging biopharma has demonstrated visionary practice in its small clinical group as the company gets close to submission. It has instituted a broad and deep review of its clinical SOPs, and fleshed them out in the many areas where they were thin. These SOPs also serve to ensure that the company's clinical program is robust right now, as it expands the scope of its candidate's indications, instead of continuing to rely on outsiders' standards. And it has also recognized the importance of creating a legitimate pharmacovigilance function, with the appropriate tools, so that it is prepared to handle internally the safety monitoring that an approved drug will require. In both cases-SOPs and pharmacovigilance-the company internalized a compliant infrastructure at modest cost for many long-term benefits.

Using the right reasons for vendor selection


My last example for the year's Pretty Good Practices is a company who has gone about technology vendor selection more efficiently than most companies do, because it focused on the right reasons for choice. Instead of spending months of intense effort to develop, define, and document the functional requirements for a clinical IT software application (i.e., how should the commands appear on tab 12), this company recognized that such actions would be reinventing the wheel. Clinical IT applications are so well defined in purpose and use that developing functional requirements for them de novo is akin to specifying how a word processor should work.

This company instead focused on business requirements: that is, what did the company need from the software and its vendor, rather than how the software should look or act. It focused on the imperatives it was facing, the skills of its staff, and the financial and time constraints of its particular development program at this point in time and the foreseeable future. These characteristics are not the same among all biopharmas; indeed they can vary greatly. And having identified what it felt was important, the company found specific, meaningful differences among the products and vendors that a functional review would never have revealed.


There are common elements in these Pretty Good Practices: boldness, speed, simplicity, and honesty. These are qualities sorely lacking in most pharmaceutical development operations. When you see them, good things are likely to follow. Whether or not the specifics of these stories apply to your company at this moment in time, these qualities will always serve you well.			

Applied Clinical Trials-12-01-2004

It's Not Our Fault, Says Drug Industry...Again

Reimbursement and Regulation Shape Pharmaceutical Research

Tech Trends Come of Age

Pretty Good Processes