New standards and research methods aim to provide more useful information on population subgroups.


The research community and federal agencies have struggled for more than a decade to obtain information about variable drug effects on patients based on race, ethnicity, gender, and age. The campaign to move away from clinical trials populated by young, healthy white males is intensifying now as more evidence emerges on how sex and race affect individual responses to medical treatment. The desire to reduce disparities in health care for racial and ethnic minorities is further heightening the need to include these populations in clinical trials, as is information on how drugs affect women and men differently. Researchers also are looking to study how drugs affect pregnant and lactating women, recognizing the difficulties of including these groups in premarket clinical studies.

The Food and Drug Administration has issued numerous guidances to encourage sponsors and researchers to collect and analyze clinical trial data from population subgroups. These include International Conference on Harmonization (ICH) standards designed to allow trials in one geographic region to provide evidence acceptable to other regulatory bodies. The National Institute of Health's Office of Research on Women's Health, established in 1990 to address concerns about a general lack of women participating in studies, now is encouraging research to assess basic cellular pharmacologic factors that contribute to sex differences in drug effect. 

This was the subject of an American Society for Clinical Pharmacology and Therapeutics (ASCPT) symposium in June. Participants examined how pharma-cokinetic (PK) and pharmacodynamic (PD) studies may provide evidence on sex-based differences in drug response and adverse events. Purdue University professor Kevin Sowinski called for more research on the underlying mechanistic issues of PK and PD differences, particularly related to pregnancy, the menstrual cycle, and menopause. IBS, cardiovascular disease, and psychiatric disorders were also discussed. 

Similarly, the Society for Women's Health Research addressed challenges and opportunities in collecting subgroup data on women in clinical trials at a meeting last October on "Clinical Trial Design for Sex Analysis." Researchers emphasized the importance of including women in early studies in order to design appropriate late-stage trials. Stanford University School of Medicine professor Donald Stanski noted that Phase III studies of tirilazad failed because the development team did not recognize early on that women required higher doses than men. Stanski and Carl Peck of Georgetown University's Center for Drug Development Science propose using quantitative techniques to analyze Phase I PK/PD data from men first and then collect data from a minimal number of women to determine the significance of sex-specific differences. 


FDA began to urge sponsors to study more women and minorities in the early '90s. A 1993 guidance called for analysis of trials by gender, including evaluation of PK data in women. This document officially ended FDA's 1977 policy that excluded women of childbearing potential from participating in early-phase clinical trials. FDA also clarified that it may refuse to file an application if sponsors fail to evaluate the safety and effectiveness of a new therapy in "pertinent subsets," such as gender, age, and race.

The FDA Modernization Act of 1997 (FDAMA) required FDA to examine the inclusion of racial and ethnic groups in clinical trials. That led to FDA's 1998 "Demographic Rule" (Regulation of Investigational New Drug Applications and New Drug Applications). It requires sponsors filing new drug applications (NDAs) to submit safety and efficacy data by gender, age, and racial subgroups, but does not specifically require inclusion of these subgroups in studies. 

Several ICH standards address issues related to subgroup analysis in clinical trials. The ICH 1998 guidance on Ethnic Factors in the Acceptability of Foreign Clinical Data (E5) aims to reduce the need for additional clinical studies in nations where a company plans to market a drug by encouraging bridging studies that demonstrate data developed in one region is relevant to another. In June 2004, FDA further elaborated in a Q&A guidance on how sponsors should evaluate which ethnic factors affect foreign clinical data. 

In addition to encouraging sponsors to collect race and ethnicity data along with sex and age data, a 1999 guidance recommends using population pharmacokinetics to find differences in drug safety and efficacy among ethnic and racial subgroups. To clarify how researchers should collect this data, FDA advised sponsors in January 2003 to use the five racial/ethnic categories of the Office of Management and Budget (OMB). FDA acknowledges that these categories reflect social norms more than scientific evidence, but recognizes the value of collecting standardized information that can be analyzed and compared by different parties. Some researchers believe, however, that data based on such categories may become less relevant in light of evidence that an individual's specific genetic variants, disease state, and multiple environmental factors may have a greater impact on drug response than race and ethnicity. FDA has received comments on this proposal and is weighing further revision.


FDA's 1993 guidance "lifted the bar" on including younger women in early trials, observed Susan Wood, director of FDA's Office of Women's Health, at the ASCPT symposium. Sponsors are enrolling sufficient numbers of women in early trials and are including gender information on product labels, according to FDA analysis of protocols and submissions. Data analysis is still weak, though, and it does not lead to changes in drug dosing on product labels. 

To facilitate more timely assessment of how well sponsors use subgroup data from clinical trials, two years ago Congress called for FDA to develop an agency-wide database of demographic data on clinical trials. This Demographic Information and Data Repository is still in the planning stage as FDA strives to establish the technical parameters for this project and align it with the agency's evolving data management system. 


Although clinical trials today routinely include multiple subgroups, pregnant and lactating women remain off most protocols. Sponsors and regulators agree that it is highly risky to include these groups in investigational programs, while also recognizing that these patients use drugs and often need more than the scant information now available on how a therapy may affect mother or child. 

Most information on drug effects on pregnant women emerges after a drug is on the market. In June, FDA cautioned physicians about prescribing anti-depressants to women in the late stages of pregnancy, pointing to new product label information about possible harmful effects on newborns. FDA also warned women against using an unapproved foreign drug that was purported to increase breast milk production, but is linked to cardiac arrests and even death. 

A May 2004 workshop on PK and PD in drugs in pregnant and lactating women sponsored by the American Association of Pharmaceutical Scientists (AAPS) addressed the challenge of designing studies to obtain useful information on this patient subgroup. Although NIH and FDA want to encourage more studies that examine drug use in pregnant women, Kathleen Uhl, Pregnancy Labeling Team leader in FDA's Center for Drug Evaluation and Research, acknowledges that researchers disagree on which drugs to study first-therapies with the most severe potential impact on pregnant or lactating women, or drugs used most frequently by these women. 

Manufacturers have conducted trials on certain drugs designed for use by pregnant woman, such as Glaxo's tests of zidovudine in reducing maternal-infant transmission of HIV, but that is the exception to the rule. FDA is unlikely to require sponsors to include pregnant women in trials, but could pressure companies to justify exclusion criteria. 

A more acceptable alternative for sponsors is to establish pregnancy registries for marketed drugs to collect adverse event data and safety signals on maternal effects. FDA requires manufacturers of high-risk products such as Roche's Accutane to establish registries and has suggested that several companies form collaborative registries for similar products. Regulators are also eyeing whether sponsor efforts to inform practitioners of pregnancy registries slip into the promotional area by implying product safety and efficacy.

FDA is updating a two-year-old guidance on pregnancy registries to clarify current policy and address new patient privacy issues. Although privacy rules allow adverse event reporting without specific patient consent, if registries are considered "research," they might require informed consent, which complicates the enrollment process. 

Another FDA goal is the development of a guidance on pregnancy-related product labeling. One aim is to define those adverse drug events that warrant listing in a separate pregnancy section of product labeling, without further overloading already dense drug labels.


The campaign to include racial and ethnic group members in clinical trials reflects broader efforts to reduce apparent gaps in minority health care services. A 2002 Institute of Medicine report on "Unequal Treatment" documented how patients from specific racial and ethnic backgrounds often receive disparate levels of care, even when they have  insurance coverage and income comparable to white patients. Senate majority leader Bill Frist (R-TN) has proposed legislation to "close health care gaps" by requiring federal programs to measure health quality by set standards that would reveal unequal care. Health care providers and insurers are also collecting data on race and ethnicity to target certain groups for special preventive health and disease management programs.-JW

SIDEBAR 2: Women, Minorities Under-represented 


Despite pressure from Congress and other groups, Yale researchers found that most multicenter cancer trials fail to enroll representative numbers of women and minorities. An analysis of participants in studies sponsored by the National Cancer Institute Clinical Trial Cooperative Group in two periods (1996-1998 and 2000-2002) shows little gain in subgroup enrollment-and an actual drop proportionally for Hispanic and black patients. The elderly also were poorly represented, considering the large percentage of older cancer patients. The study in the Journal of the American Medical Association (June 9, 2004) raises questions about what is an optimal degree of representation by minorities and other populations groups, and how to achieve that goal.-JW            

Articles

View from Washington

Sex and Race in Clinical Trials

Dismay over the level of anti-pharma feeling in the EU is not just "crying wolf."


"You have to be kidding!" Hearing that is a familiar experience for many European clinical trials professionals when they spell out some of the operating conditions for clinical trials in Europe to world colleagues. It is often hard for those not working in Europe to grasp quite how many barriers to innovation and creativity there are in Europe's regulatory and political climate.

The alternative frustration that Europeans suffer when recounting abroad their difficulties at home is: "Ahhh, you're always saying that!" Like the shepherd boy who lost all credibility by crying wolf too often, Europeans are frequently met by weary dismissiveness when they list the obstacles that hamper their efforts to bring new medicines to patients. "Europeans are always moaning," runs the oft-heard refrain.But the reality is that things in Europe are not good-and they are not getting better. Neither the clinical trials community, nor the pharmaceutical and medical sectors it serves, can be confident of the future. The virtues they have all been built upon, of energy, enterprise and excellence, may not continue to be prized.

As the most superficial example, just take the triumphalist tone of the Medicines in Europe Forum this month, in its guarded welcome for the new EU rules on medicines. This organization is run by well-meaning people proclaiming the supremacy of the patient and the citizen. But it is polarizing the debate about medicines in Europe in a way that does not better the climate for improved provision of medicines.

"For more than two years the pharmaceutical majors and their lobbyists took it for granted that they could obtain made-to-measure legislation supporting their own narrow financial interests, with scant regard for public health or for the economic survival of national health care systems," says the Forum in the July-August issue of the French magazine 

"What we achieved," continues the Forum, "was a major change of perspective: in the end, European legislators endorsed the view that medicines are not just another consumer good." It goes on to list what it sees as improvements that it won in the EU approach to regulating new medicines-and makes clear its view that Europe is changing to accept the Forum's point of view: "In future, 'Europe' will be increasingly synonymous with welfare and public services, chief among which is health care," it predicts, content to consign to the past a Europe geared to developing trade and the promotion of wealth creation. And, it warns, "many battles remain, given the inevitable clashes between major financial interests and basic human health needs." It concludes ominously with a promise that "We stand shoulder to shoulder with all those defending accessible, high-quality health care."

What is disturbing is the unquestioned assumption that the interests of citizens and patients are diametrically opposed to the interests of the industrial sector that provides medicines for patients (to say nothing of jobs for citizens). Legitimate debate starts to lose all sense when "accessible, high-quality health care" is perceived as something utterly distinct from-even mutually exclusive with-the well-being of the pharmaceutical sector.

The "successes" claimed by the Forum in modifications won in the new EU drug rules reinforce this artificial distinction. 

Greater public access to product documentation and publication of penalties for companies that don't comply with the rules are just two of the minor amendments the Forum hails. More serious is the rationale for these changes: "If citizens remain vigilant to ensure that these measures are fully and durably implemented, medicines agencies' notorious secrecy will be a thing of the past," it remarks with open hostility.


Similarly, the Forum greets with glee new conflict of interest provisions for regulators. "Currently, medicines agencies' main sources of funding are the fees paid directly to them by pharmaceutical firms, notably for evaluating marketing applications. As the experts who work for these agencies are also often involved in assessing drugs on companies' behalf, drug companies wield considerable influence over medicines agencies' decisions," it says, rejoicing over the additional measures on public declaration of financial interests by the staff who grant marketing authorizations.

Industry suspicion is also the reason for the Forum's welcome of more independence in pharmacovigilance supervising and the publicly accessible European medicines database. "These obligations may appear to represent the strict minimum. But at a time when drug  companies are funding more and more public-sector activities, these obligations are a major victory for those seeking to ensure that medicines agencies are and remain independent," it claims.

And the retention of long timelines for drug assessment procedures is perceived as "another victory for EU citizens," just because companies-and the European Commission-"were seeking a shorter period." So "(d)espite drug companies' lobbying to have their products authorised more rapidly, only the time allowed for certain administrative tasks has been shortened. In principle, the scientific assessment should not be botched because of unreasonably tight deadlines," says the Forum.

The Forum even presents one of the few direct references to clinical trials in the new rules as a victory for citizens and a blow against the pharmaceutical industry. "An important document has now been added to the list that applicants must provide (for both national procedures and the European centralised procedure)" it states regarding the rule that clinical trials carried out outside the European Union meet the ethical requirements of the EU's new clinical trials rules (Directive 2001/20/EC). "Thus, the principles of [the Directive] must be followed, with respect to the protection of participants, ethics committee and adverse event reports, even when a drug intended for the European market is tested outside the EU," crows the Forum.

Equally eloquent testimony comes from the Forum's "failures." "Pharmaceutical majors, with support from the European Commission's Enterprise Directorate General, succeeded in ensuring that the notion of 'added therapeutic value' will not be taken into account when considering whether or not to authorise new drugs, and that the 'clinical protection period' will be even longer than before," it says. And it issues another dire warning couched in quasimilitary terms: "EU citizens must remain mobilised to ensure that the texts are effectively enacted in national legislation and are strictly applied in patients' best interests. We must also be on the lookout for the tricks that the drug companies will inevitably employ to preserve their financial interests."

It regrets that there was nothing more than "lip-service to the notion of 'added therapeutic value.'" No comparative clinical evaluation is required to determine whether a new drug offers a real therapeutic advance relative to reference drug or nondrug treatments, it laments. But there are sufficient allusions to that concept in the new rules for the Forum to conclude: "The comparison of new drugs with available reference treatments, long demanded by patient groups and health care professionals, but rejected by pharmaceutical firms, finally appears in the European regulation on medicinal products. This comparison is not obligatory prior to marketing application, but at least a small step has been made in the right direction."

The Forum's most virulent criticism is reserved for what it depicts as "Industrial protectionism: a victory for drug companies." Certainly the question of for how long clinical trial data should be protected was one of the most contentious issues in the EU debate on these new rules. The Forum is not only disappointed at the outcome, but outraged at what it sees as the consequences for health care supply.

"Drug companies employed all the means at their disposal to prolong the period during which their drugs are protected from generics," it says. "After two years of intense debate and infighting between the powerful pharmaceutical majors and the less powerful generics manufacturers, clinical trial data protection in Europe was harmonised towards a longer period." 

And protectionism has been aggravated, it charges, by "the invention of 'biogenerics.'" The definitions of  generics and biogenerics "have been rendered sufficiently vague and complex to make it more difficult for generics manufacturers to obtain marketing authorization. In particular, it will be more difficult to avoid conducting new preclinical and clinical trials when the manufacturing process (especially when based on biotechnology) is only slightly different from that used for the originator product." 

The views of the Forum-which is  often aligned with the generic pharmaceutical industry-border on the actionable. "The money spent by pharmaceutical majors to influence deputies and ministers, and to spread malicious rumours on the potential risks of generic drugs, was well invested. Welfare organisations and mutual health insurers will soon feel the economic pinch," it warns. "The pharmaceutical companies have won a major victory for protectionism," it concludes. 

The Medicines in Europe Forum is no isolated extremist group on the fringe of politics. It is a coalition of patients, consumers, health professionals, and health insurance organizations with a growing influence on the real world of European politics.

Of course, the Forum is not the only force in European affairs. Nor is it the principal force. But it is remarkably representative of the forces that increasingly shape Europe's destiny. It is characterized by hostility to the profit motive, suspicion that big business is in an unholy alliance with the authorities, skepticism about the merits of science and technology, and an assumption that it is more noble to focus on equitable distribution of assets rather than on the creation of wealth-an attitude frequently struck in conjunction with high moral claims to defend the interests of citizens, consumers, or society as a whole.


At the level of the pharmaceutical industry, the alarm is being raised again. The new annual report of the European Federation of Pharmaceutical Industries and Associations gives further evidence: "since the early 1990s, the research-based pharmaceutical industry in Europe has been losing competitiveness with respect to the U.S. Data for 2002 and preliminary figures for 2003 confirm the vulnerability of Europe's research-based pharmaceutical industry. Benchmarking and performance indicators show that the U.S. has continued to increase its relative position as a locus of innovation." Market evolution has "particularly benefited U.S.-based companies which have significantly increased their share in sales of new medicines and development of new molecules." 

In conclusion, "As a whole, Europe remains less attractive for R&D investments than the U.S. The economic and regulatory framework, the science base, the investment conditions, and societal attitudes towards new technologies all contribute."

A key priority for EFPIA is to promote and develop Europe's pharmaceutical science base. It has set up a new group of research directors to help plan how to fight the current brain-drain by attracting and retaining the best scientists in Europe. "We must secure a vibrant and innovative science-based industry in Europe that delivers breakthrough treatments which European patients rightly deserve," according to Jonathan Knowles, the new group's director. And a key element in improving the competitiveness of the research-based pharmaceutical industry in Europe is in creating a regulatory and political environment which stimulates R&D in Europe and rewards innovation.

The challenge facing the clinical trials and pharmaceutical sector is widely reproduced across Europe. The long-term EU plan of creating a competitive economy by 2010 is-by common consent-running into the sand even before the midpoint review due next year. Meanwhile, report after report demonstrates the failure of key EU economies (notably Germany and France) to carry out the structural reforms necessary to boost growth and stimulate competitiveness.

For those whose intuitive response is "You have to be kidding!" or "Ahhh, you're always saying that," remember the end of the shepherd boy fable. When the wolf finally appeared, the boy's cries for help went unheeded, and he and his flock fell prey to the marauders from the outside world.            

View from Brussels

EU Climate: Pharma Health Is at the Patient's Expense

Move away from the "service" model if it means being subservient.


For many years now, it has been fashionable to work on corporate processes by encouraging a "customer-vendor" relationship between departments. I have been as guilty of this as anyone. In listening to the problems facing clinical development departments recently, however, I have come to realize that this concept is either misapplied, misunderstood, or simply a mistake. Unless great discipline is exerted on all sides, "customers" are poorly served and "vendors" are exploited.


The original concept of treating each other like we are each other's customers is drawn from many good intentions, and merges many process improvement philosophies and techniques. At my company, we use a "voice of the customer" technique, for instance, which emphasizes this style of thinking. TQM (Total Quality Management) teachings of various flavors use this terminology. Process Mapping-the visualization of complex workflows-is sometimes presented in this fashion: Who is your customer? Whose customer are you?

In many ways, talking about each other as customers is not unlike the Golden Rule: treat your organizational colleagues the way you would want to be treated. Using terms like "customer," "vendor," and "service" puts a warmer face to "inputs/outputs," or "deliverables."  

Customer orientation as a corporate process concept was long overdue when it first appeared. Most companies-pharmaceutical companies among them-desperately needed to overcome the detrimental "silo" ideas to eliminate the pointing fingers of blame, and to show the interdependencies people share in a complex organization.Examples of such poor relationships at pharma companies were (and still are) legion: between clinical operations and clinical data management, biostatistics and medical affairs; regulatory affairs and product marketing; investigative sites and monitors (CRAs); chemists and pharma-cologists; informatics and everybody.

But there are problems with this kind of language. For instance, if everyone is everybody's else's customer, is anybody "making" anything, or are we all just "buyers" expecting to be served? In fact, not everyone is a customer of someone else. Sometimes, for instance, people are other people's bosses. Sure, you can treat your boss as a customer, but it may be more important to follow his or her leadership rather than think about delivering him/her a service. Sometimes our colleagues are simply sources of money, or data-neither customer nor vendor. And sometimes we have nothing to do with each other, but if the mantra of customer-vendor is too ubiquitous, the corporation may be insisting that these folks develop a time-wasting connection in the blind pursuit of popular jargon.


More importantly, there are two fatal flaws in the everyone-is-a-customer approach. First, even given the legitimacy of the concept, the true "customer" of our work may in fact be at a much higher level than who we are trained to serve. For instance, the customer who is worthy of that name may not be the next person in the handoff chain, but rather the Clinical Development function as a whole, or your biopharmaceutical corporation, or the regulatory agencies, or even the patients you hope to help. Unfortunately, the customer focus approach almost exclusively encourages a pragmatic, heads-down, make-the-next-guy-happy mentality. This may not actually help your organization at all, if the focus should be at a much higher plane. 

Secondly, the concept of "service" is misused. If we have customers, then we are supposed to "serve" them. This is where the customer concept can get really deadly. When we start to think about "providing a service," and then turn this into "being of service" to our customers, if we are not careful we can end up being "subservient." These words all sound pretty similar, but subservience means being a servant; it implies that the customer is better than we are, or more importantly, subservience means the customer's needs are more urgent than ours. It doesn't have to be this way, but when we overlay the customer focus superficially and without diligent rigor on age-old interdepartmental rivalries, that's what we end up with.

 Clinical Data Management "vendors" take the customer focus philosophy to heart and concentrate on serving the clinical study manager. In doing so, they are forced to choose between losing their carefully built-up standards, structures, and efficiency, to serve the study team with flexibility. 

 Monitors focus so much on sites (their customers) that they allow consistently poor site performance in enrollment and data quality for the sake of "satisfying" that Key Opinion Leader.  

 Clinical operations is intimidated by its site "customers" into paying them more to use EDC (electronic data capture)-a tool which will in fact lower site workload if used correctly. 

 Biostatisticians give their physician customers in Medical Affairs everything they ask for despite what this does to the timeline, or despite the fact that the data may not yet be properly cleaned or of sufficient volume, or that the questions the physicians are asking take the company's eye off the ball. 

 Clinical operations tries "serving" CDM, and in trying to meet CDM's stringent view of data cleaning, ends up with an inefficient monitoring schedule and that classically unnecessary task: 100% SDV (source data verification).

In fact, having customers and serving them are not inextricably linked. It is possible to be customer-focused and yet not be subservient to your customers.  "The customer is always right" does not mean that the vendor is always wrong. 


One way of looking at "customers" without becoming subservient is to see each other as equals, not servants. After all, if everybody is somebody's customer, we are equal. And equality brings several characteristics into play which are very healthy for a corporation: mutual respect, boundaries, expectations with limits, and a common multilateral goal, not a linear production line goal. It allows the Clinical Development department to focus above the level of the next handoff, and concentrate instead on the plan, the submission, or the patient. And it ensures that each profession can determine which of its values are corporate-critical.

How do we get to be equals? Good will and strong leadership are certainly essential, but human behavior and entrenched practices often require a little extra help to change. Fortunately there is a well-established concept in this regard: the Service Level Agreement (SLA).

SLAs are an invention of our service economy, and while they have been used in many industries, the concept is not widely applied yet in pharmaceutical firms, especially in drug development. An SLA looks very much like a contract. It spells out responsibilities, timelines, expectations, deliverables, authority, change procedures, and problem resolution. As such, it documents what one may have documented in a Process Mapping exercise, but does so in the language that societies have developed over centuries to bind people to a common purpose.

Initially, people often react badly to this concept. Why do we need a contract when we have worked together for so long? Why don't you trust me/like me anymore? Spiteful behavior can ensue: "Well, if you're going to write that down, I'm going to write down this!"  "If you want this done on time, how about you doing this for me on time!" And as petulant as these sound, this is exactly the point. The SLA becomes a tool to generate an open dialogue that, without it, simmers below the service. The SLA's formality uncovers flaws, resentments, or missed expectations that were never articulated otherwise.

In the end, by going through this process, you may not need the formal document-just trying to write one may be therapeutic enough. But we are so increasingly interdependent across clinical development, and across all pharmaceutical company departments. This documentation of how that interdependency will be managed to both the corporate good and the successful treatment of patients may be necessary, at least for a few years, until old habits die off and mutual respect and understanding become second nature.

When your waiter tells you "I will be your server tonight," he or she represents in fact a range of products and services-the chef's creativity, the cook's execution, even the delivery truck that brought the raw materials. And you have your responsibilities as well-to arrive at the restaurant on time, to know what you like, to treat the staff well. The delicate flavors, the perfect ambience, a lovely wine are all the result of a combination of lots of people providing you a terrific meal, plus your ability to be ready to enjoy it. They are not your servants, and you are not a burden for them to bear. And as equals, server and served, customers all, we can go home well satisfied with a meal, and a job, well done.            

Process Improvement

Not at Your Service


The June 2004 article "Meeting the Challenges of Internet-based Clinical Trials" describes the current state of the art of Internet-based clinical trials. Just to ensure that the technologies do not rest on their laurels, the next generation of technology-e-source documents-will truly revolutionize clinical research. 

E-source documents will eliminate batch processing of data and almost all manual transcription, the presence of which guarantees an inefficient and error-prone data capture and reporting process.

Here is my wish list for e-source document technology: 

  Handwriting and voice capture for progress notes

  Real-time optical character, voice recognition, and progress note transcription (in a low-wage country)

  Real-time access to the informed consent form, protocol, investigator's brochure, etc. 

  Automatic time reporting (how long do study activities really take?)

  Real-time integration with sponsor's database for sophisticated data validation and queries

While we're at it, it's time to rethink the source document. Using current source documents is like singing a song with the words on one page (the source document) and the notes on another (the protocol). With a combined "scripted source document," we can eliminate a lot of wasted time and errors by integrating step-by-step protocol instructions with data capture fields.

All the technology to implement scripted e-source documents exists today. What are we waiting for?

Letters to the Editor

Readers respond to articles and columnists.

he international pharmaceutical industry is considered to be highly successful, having launched nearly 1,400 new molecular entities (NMEs-compounds that have not previously been made available as human therapeutics) over the last 30 years.

  At present, U.S. and European pharmaceutical companies are seen as the leaders in terms of new drug development. But Japanese companies have also made a steady contribution to global drug output, with their peak of success occurring between 1992 and 1995

One of the major indicators of the international pharmaceutical industry is the number of new drugs reaching the global market. If companies are to remain profitable and wish to justify to patients and governments the high prices that they charge for their medicines, they must demonstrate that their considerable R&D investment results in new medicines. In 2000, the pharmaceutical industry was estimated to have spent $58 billion on R&D, with around 40% of this devoted to clinical trials.

In recent times, there has been concern that the productivity of the major companies has been decreasing. Many of the major companies in the industry have received criticism that they lack new ideas and methodologies. They assert that the industry is producing too many similar new drugs that offer little clinical advantage over those already on the global market. 

 Figure 1. Number of NMEs launched globally (1992-2002). 

Even some within the industry itself have expressed concern over current productivity rates, speaking of an "innovation deficit" in pharmaceutical R&D.

  They have questioned whether companies are relying too heavily on line extensions and new drug delivery systems and formulations, rather than on developing novel compounds. One study carried out in 2000 found that major companies were spending a third of their R&D expenditure on line extensions.

Although global pharmaceutical R&D expenditure increased by 121% between 1990 and 2000, the number of innovative new drugs reaching the marketplace has steadily declined.

  In 2002, the lowest number of novel medicines launched into the world market in over 20 years

  (Figure 1). Twenty-eight NMEs were first launched in 2002, a number that is almost half of the corresponding figure for 1997.

  In 2001, the corresponding figure had been only 31 NMEs.

  The situation was not predicted to improve through 2003, as the decrease in new medicine launches was accompanied by a decrease in new medicine applications within the major regions. During 2002, the FDA, EMEA, and MHLW all reported a fall in submissions.

Worrisome for the industry, as the cost of clinical development has increased there has been little sign of improvement in drug attrition rates. In a survey of major pharmaceutical companies, CMR International found that mean clinical evaluation expenditure increased from 32.5% in 1996 to 39.5% in 1998.

  In its 2002 survey of U.S.-based companies, PhRMA noted that the inflation-adjusted increases in clinical R&D costs were more than five times greater than the costs for preclinical work.

  Yet despite the efforts made by companies to improve success rates, it is estimated that only 15% of new drugs entering development will subsequently reach the market.

  Even at the latter stages of clinical development, failure rates are less than ideal. Success rates from Phase III to market can range between 50% and 70%.

To some extent, a clinical R&D expenditure increase is to be expected. Many of the new drugs in clinical development are focused on newer and more difficult disease targets, which will lengthen the overall R&D process due to complex trials. For example, a number of new treatments are being developed for CNS disorders such as Alzheimer's and Parkinson's diseases, where there is a lack of effective treatments.  

An analysis of the development times of 574 new drugs that first reached any one of a defined 20-country market between 1984 and 1999 showed that new chemical entities for CNS disorders had the longest overall development times, with a mean of between 12 and 14 years.

  The difficulties in developing new chemical entities for CNS disorders were highlighted by comparisons with other therapeutic classes. In the same analysis, development times for cancer drugs ranged from 10.5 to near 12 years, where those for anti-infectives ranged from 9.6 to 11.7 years.

Given the heavy R&D investment and global presence required for success, many observers have overlooked the Japanese pharmaceutical industry as a source of innovation. One of the reasons for this is that Japanese pharmaceutical companies have a relatively low spend on R&D compared with western companies. This has also led to a view that Japanese companies have previously concentrated too heavily on "me-too" products.

  It is estimated that the average R&D budget of the top 10 Japanese pharmaceutical companies are about 20% of the average for the top 10 western companies.

Figure 2. Success rates in developing NMEs for 17 Japanese companies (1992-1996).   

In its survey of 17 local companies, the Japan Pharmaceutical Manufacturers Association (JPMA) found that between 1992 and 1996 for each NME submitted for approval to a regulatory authority, 1.6 had entered clinical studies; and for each NME marketed, 1.9 had entered clinical studies.

  This 53% dropout rate in clinical development represented the most substantial loss in R&D investment for Japanese companies.

  However, in spite of such risks (Figure 2), Japanese companies have shown a strong commitment to clinical research. In its 1996 Japanese pharmaceutical industry survey, the JPMA found that its member companies had started 23 clinical studies that year, but that in 2000 its members had started 42 such studies. Over the five-year period 1996 to 2000, its members had started a total of 162 clinical studies and had submitted 82 new drug applications (NDAs).

Clinical development is expensive and risk-intensive, so it has sometimes been assumed that Japanese companies would be content to remain within their home market, but many of them are now openly seeking partnerships to help them internationalize their innovative research. TAP, Takeda's joint operation with Abbott, and Eisai's partnership with Pfizer for the sale of its Alzheimer's drug Aricept are two examples of such partnerships. Another option for Japanese companies is to use the services of a contract research organization (CRO). Outsourcing has been in-creasingly utilized by international pharmaceutical companies, as illustrated by the fact that of the $30 billion that the U.S. pharmaceutical industry invested in R&D,

  between 20% and 25% of this was spent on outsourcing.

The quality of Japanese pharmaceutical research is considered high, and a number of important international drugs have their origins in Japanese R&D. These include Bristol-Myers Squibb's Pravachol (pravastatin) for high cholesterol, TAP's anti-ulcer drug Prevacid (lansoprazole), and Daiichi's antibiotic Levaquin (levofloxacin).

  More recent examples include AstraZeneca's lipid-lowering drug Crestor (rosuvastatin calcium), which originated at Shionogi; Bristol-Myers Squibb's Abilify (aripiprazole) for schizophrenia, the result of a collaboration with Otsuka; and Eisai's Alzheimer drug Aricept (donepezil hydrochloride), co-marketed with Pfizer.

Japanese pharmaceutical companies, like other Japanese technology industries, are beginning to take a more global outlook. Given their innovative capacity, they have much to offer in terms of new drug productivity. For example, in 2001, a year when a number of major Western companies failed to contribute to the global output of 31 NMEs, Mitsubishi Pharma Corporation launched two brand new drugs.

  Far from being "me-too" products, these were innovative drugs: Radicut (edavarone) for acute-stage cerebral infarction and Cleanal (fudosteine) for chronic obstructory pulmonary disease.

In 2002, Japanese companies were responsible, either through partnerships or on their own, for the launch of seven new molecular entities-classified by CMR International as products which had never before been available for therapeutic use in man

  (Figure 1). The Japanese products launched in 2002 covered the infectious disease, inflammation, oncology, CNS, and cardiovascular therapeutic areas.

Although Japanese companies are involved in a broad range of therapeutic areas (Figure 3), some have become increasingly focused on disorders common in the elderly. Health care for the elderly has become an important issue for industrialized countries, particularly where governments share much of the expenditure on medications. According to the Organization for Economic Cooperation and Development (OECD), the over-65 age group require four times as much health care resources as younger people.

  OECD simulations have suggested that between 2000 and 2020 annual health care spending for industrialized nations will grow between 0.4% and 0.7% as a result of aging.

  By 2005, it is predicted that over 25% of the world's population will be over 65.

  Pharmaceuticals will play an important role in health care for the elderly, and thus the results of clinical trials will be important for Japanese companies to prove that their products are better than those already offered.

Figure 3. Regulatory categories for medical device in the European Union. 

An example of this situation recently took place in the United Kingdom in 2001, where a ruling was made by the British government's National Institute of Clinical Excellence (NICE) to make Eisai's Aricept and certain other Alzheimer's disease treatments freely available on the National Health Service (NHS) to patients with mild and moderate forms of the disease. The role of NICE is to provide patients, health professionals, and the public with official clinical guidance on current best practice for medical treatments, and it achieves this through independent reviews of clinical and economic evidence. NICE's decision was backed by a U.K. patient organization, the Alzheimer's Disease Society, which campaigns for U.K. patients to have access to medical treatments on the NHS. 

One area with possibilities for innovation in drug development is the biotech sector, which is dominated by U.S. and European companies. Biotechnology promises many benefits, such as medical treatment tailored to the individual patient's biological make-up. Although it has been estimated that the number of biotech companies in the United States is 25 times that of Japan, according to Ernst & Young, the Japanese biotech sector should experience strong growth in the next few years, partly because of continuing government support.

  For example, the government selected genetic research as one of the key areas in its eight Millennium Projects. These are joint industry-academia- government projects, and have around  $1 billion in funding allocation.

  There has also been a recent change in Japanese law, which allows faculty members at national universities to serve simultaneously as corporate executives in start-ups.

  This will be a major boost to start-up companies and should lead to a focus on biotechnology in Japanese new drug development.  

Furthermore, investments by Japanese pharmaceutical companies in biotech research will drive this area. In 1999, Kyowa Hakko and Mitsubishi Chemical formed a joint venture company called Gencom to use gene technology to develop new drugs.

  With the assistance of the Japan External Trade Organisation (JETRO), which matches foreign companies with their Japanese counterparts, many U.S. biotech firms are in talks with companies in Japan about possible alliances.

 Japan companies and international clinical research

The conditions for Japanese companies to carry out clinical development abroad now are much better than they have been. The International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) has been a strong driver in this regard. ICH aims to eliminate duplicate studies and promote global clinical development, with the anticipated impact of further reducing development times and costs.

  ICH is a unique project that brings together the regulatory authorities and pharmaceutical industry experts of Europe, Japan, and the United States to discuss scientific and technical aspects of product registration.

One of the most important initiatives has been the introduction of the ICH E5, the Ethnic Factors in the Acceptability of Foreign Clinical Data guideline. The  ICH E5 guideline describes regulatory strategies that further facilitate the acceptance of clinical data between the different ICH regions. It also covers the use of bridging studies, if necessary, to allow extrapolation of data and development strategies with respect to ethnic factors

  (Table 1). The guideline was adopted in March 1998 by the European Union's (EU) Committee for Proprietary Medicinal Products (CPMP) and by the Japanese Ministry of Health, Labor and Welfare (MHLW) in August 1998 and was published in the Federal Register by the U.S. FDA in June 1998.

Figure 4. Japanese pharmaceutical companies: overseas employees by region.

Until the introduction of this guideline, lengthy repeated clinical trials were often unavoidable for pharmaceutical companies if they wished to market a drug in more than one ICH region.

  The ICH E5 guideline has been used with some success to streamline clinical development for Western companies wishing to bring their products to Japan, and it is expected that Japanese companies will be able to use the guideline in bringing their products to the United States and Europe.

Japanese companies are increasing their presence abroad, and JPMA figures show that a greater percentage of sales are coming from overseas than ever before.

  In a 1998 survey of its members, less than 12% of sales were coming from abroad, but by 2000 this increased to nearly 21%.

  However, this overseas presence is not just focused on marketing. During this time, the member companies had also increased the number of research institutes and manufacturing plants they established abroad, and had increased staff numbers at these locations

Yamanouchi is one Japanese firm that has been transforming itself into a more global company, having established additional operations in North America, Europe, Asia, and South America through the late 1990s. The launch of tamsulosin in the Netherlands under the trade name Omnic was considered highly significant, since this was the first Yamanouchi product to be clinically developed and marketed by the company in Europe.

Globalization has become key in Fujisawa's company strategy. In 1999, it announced "Vision 2005," a long-term management policy aimed at carrying the company's growth toward 2005 and through to 2010.

  As part of this plan, Fujisawa aims to be a global company, competing with major global companies in targeted therapeutic areas. It aims to have sales of Â¥400 billion by 2005 (split 50/50 between Japan and overseas).

  At present it has approximately 350 people working in clinical development in Europe and the United States, where it is carrying out three Phase III trials and 12 Phase II trials.

One of the reasons for carrying out clinical trial work in the U.S. and Europe has been to give local clinicians the experience of working with Japanese products as they are developed. This will be important if Japanese companies are to be successful in these major medical markets. The focus on Europe and the United States for clinical research has also been driven by a perception that the clinical research environment in Japan is lagging behind. 

As with other countries, there have been some medical controversies in Japan that have not helped to promote a good environment for subjects to participate in clinical research.

  Patient understanding of the objectives of clinical research and their trust in those that carry it out remain widely discussed issues. Subject recruitment is already a major issue in running international clinical trials, and thus improving the situation in Japan is in everyone's interest. 

Aside from subjects, certain industry figures have openly called for changes in the clinical research environment in Japan. For example, JPMA's President Osamu Nagayama noted at a 2001 news conference that incentives in the U.S. hospital system for clinical research with the industry continued to be better than those in Japan.

  He remarked that at most Japanese hospitals, the system for clinical trials was not organized and that this situation was particularly serious at state-run hospitals.

  He called for formal systems to be established that would allow researchers and their teams to earn incomes from the conduct of clinical trials.

  If Japanese companies believe that they have better chances to run trials in the United States and Europe because of concerns over subject participation and the clinical trial infrastructure in Japan, then the impact of changes currently being made to the Japanese system will be lessened.

Table 1  Ethnic factors as defined by the ICH E5 guideline(20)  

There is no doubt that Japanese pharmaceutical companies have a capacity for innovation in new drug development. They are involved in key therapeutic areas and already have a track record of bringing products to the market. However, many are now at a stage where they have openly taken steps to globalize, which will require different research and commercial strategies to rival multinational companies in foreign markets. In particular, the U.S. market is the leading world region for pharmaceutical research and is highly competitive. Most major international companies believe that success here is necessary to drive further growth and thus future research efforts. In Europe, knowledge of the differences between individual countries in terms of clinical practices and regulatory processes, and how these relate to certain European-wide guidelines such as the EU Clinical Trials Directive (2001/20/EC), will be essential for success. 

One means by which Japanese companies have sought to operate in these regions is to partner with other local R&D-based organizations to share risk and to benefit from the experience of their partner. Other companies have slowly developed themselves in the United States and Europe over a period of years and have formulated specific strategies for their future operations based on the knowledge they have gained during this time. 

Given the pressures that all pharmaceutical companies face, it will be telling to see which Japanese companies have the right strategy to be consistently successful in negotiating the hurdles of clinical development and launching innovative new medicines on an international basis.  

1.F. Kermani and G. Findlay, "The Pharmaceutical R&D Compendium," (2000); available at http://

2. J. Drews, "Innovation Deficit Revisited: Reflections on the Productivity of Pharmaceutical R&D," 

3. M.S. Ogg, M.A. van den Haak, R.G. Halliday, "Activities of the International Pharmaceutical Industry in 2000," CMR International (2001); available at http://

4. P. Sculthorpe and D. Lowman, "New Medicine Launches 2002," CMR International (2003); http://

5. F. Kermani and M. Van den Haak, "Drug Development 2001," CMR International (2002); available at http://

6. "Industry Profile 2002," The Pharmaceutical Research and Manufacturers of America (PhRMA); available http://

7. G. Ashton and F. Kermani, "Getting to Grips with Attrition Rates," 

 (2002), 20 (1), 8-9, CMR International; available at http://

8. D. Jack, "The Japanese Pharmaceutical Industry: Hard Times, Tough Decisions, but a Strong Game Plan," 

9.  R.G. Halliday, "Japan in Focus: Strategies for Innovation and Global Drug Development-What Differentiates Japanese Pharma Companies from their Western Counterparts?," CMR International (2001); available at http://

 Japan Pharmaceutical Manufacturers Association Data Book 1997-1998

11. "Pharmaceutical Outsourcing Trends: An Analysis of the CRO Market Opportunity to 2006," UBS Warburg (November 2001). 

12. "IMS Health Reports 11% Growth in Retail Pharmacy Drug Sales for the 12 Months to April 2002" available at http://

13. M. Nakamoto and D. Pilling, "Pharmaceuticals 2001/Japanese Focus," 

14. "Abilifyâ¢  (Aripiprazole) Approved by U.S. Food and Drug Administration for Treatment of Schizophrenia," Bristol-Myers Squibb press release (Nov. 15, 2002). 

15. U.-G. Gerdtham, B. JÃ¶nsson, M. MacFarlan, H. Oxley, "Factors Affecting Health Spending: A Cross-Country Econometric Analysis, in New Directions in Health Care Policies: Improving Cost Control and Effectiveness," Organization for Economic Cooperation and Development (OECD) Paris, OECD/GD (94) 101 (1995). 

16. "Population Aging-A Public Challenge," World Health Organization: http://

18. "Japan Biotechnology Industry," Biotech Japan; available http://

19. "Ethnic Factors in the Acceptability of Foreign Clinical Data E5," International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH); available at http://

20. C. Anderson and F. Kermani, "Global Acceptability of Clinical Data-Fact or Fiction?,"

Feature Article

Long overlooked as global drug innovators, Japanese pharmaceutical companies are gaining attention for their novel clinical development programs.

Japanese R&D: Branching Out

he explosive costs associated with today's clinical trials require a very high level of scrutiny to weigh their scientific and regulatory merits prior to their commencement. However, passing the regulatory hurdles in order to obtain a marketing license does not always fully coincide with providing the necessary clinical information to place a new product in its intended context. Phase IIIa studies are therefore often not sufficient from a public health viewpoint, and additional Phase IIIb and IV trials need to be considered. This article gives a review of some of the regulatory challenges associated with later-phase development and highlights opportunities to participate in the formation of guidelines. 

While various definitions of what Phase IIIa, IIIb, and IV constitute are in use between various agencies, academic centers, and companies, the following definitions are used in this article for the purpose of clarity:  

 The efficacy and safety trials that are conducted with the primary purpose of filing for a marketing authorization (MA) of a particular product with the relevant authorities. 

 The efficacy and safety trials that support the initial claims made by the future marketing authorization holder. 

 Additional studies that are conducted to increase patient exposure; these additional data are either provided to the authorities at the time of approval or, because the studies are typically not completed at the time of initial filing, will be submitted as a postapproval commitment. 

 Studies with focus on new indications, new comparators, new efficacy endpoints, efficacy assessed by new methods, etc. after MA has been obtained. 

These definitions are not universally recognized. Most regulatory agencies do not make a distinction between Phase IIIa and IIIb, and some companies use the concept of a Phase V that would fit under the definition of Phase IV above. There is also considerable overlap. Some studies are conducted to provide information that can be used to promote a drug at the time that a license is granted, such as a study in a special population or under special circumstances. When studies are initiated before the filing for a license, they are to be considered Phase IIIb studies, but there is often clear similarity in objectives or design to Phase IV studies.

The results of a Phase IIIb study are, as previously stated, typically not available at the time of initial filing for a license. The results must be presented to the regulatory authorities when available. Furthermore, the authorities must be informed of the status and kind of all additional ongoing incomplete studies at the time of application submission. 

It is estimated that out of every 10,000 molecules discovered, synthesized, and screened, only about 50 are found to have potential as a drug and progress to preclinical in vitro and animal testing. Further, only 10 make it to Phase I and just three make it to  Phase II, leading hopefully to one product that can get licensed as a human medicine. As Figure 1 illustrates, the basic research takes on average 3 to 7 years, the clinical development an additional 4 to 8 years, and registration another 1 to 2 years for an accumulated average of 10 to 14 years on a product that is granted a 20-year patent.

This long lag time between the development of a concept to roll-out of a new product is exceptionally long compared to other industries; in the car industry this is typically in the range of  2 years, in the software industry less than 18 months. This lag time adds to the investment burden.  

According to a May 2003 report from the Tufts Center for the Study of Drug Development,

  the investment to develop one new product is now on average almost $900 million (

 730 million or Â£500 million), with clinical development expenses increasing in particular. It is thus fair to say that the development of new drugs for humans is a high-risk process that requires a very high investment over a long period of time, with severe attrition rates of initially screened compounds that may lead to very few licensed products. This explains why there is a tendency to bring these new products to the market as soon as safely possible despite a progressed stage of development, as the anticipation of the public and the industry is great. 

In the current high-risk environment, priority is given to develop drugs in possibly contradictory categories: drugs that are safe, that belong to franchises that correspond to the highest public health needs, with few or no competitors, and with achievable targets to fulfill all regulatory requirements. Unfortunately, many of these factors oppose further development and can lead to program shutdown when the risk is deemed too high.  

There are ongoing and considered initiatives underway to tip the balance more favorably back towards development, such as accelerated Phase II and III trials, shortened review time to obtain licenses, and added data protection times. As Figure 2 shows, it still takes an average of 1.5 years to obtain a marketing approval in most major markets despite many sincere initiatives to shorten approval times. Figure 3 shows detailed registration times for Centralized Procedures with the European Agency for the Evaluation of Medicinal Products (EMEA), confirming a 1.5-year average, with nearly half of the time used for assessment by the agency, an equal amount to respond to questions by companies, and limited time for the decision-making process and administration. As a result, major changes are unlikely given the complexity of drug approval. It has been well discussed that while detection of new chemical entities is fairly steady when seen over a longer period, the costs have been rising over the last decade while the actual number of products has been falling. This trend is unlikely to reverse.  

From both public health and marketing points of view, it is very important to get new therapies to patients as soon as safely possible. An important aspect in late-phase development is how to obtain early MA for the product. This is the focus of Phase IIIa studies, often based on science and regulatory requirements that differ from country to country.   

The choice of a comparator drug is a good example of the challenges. The current medical practice drug, the gold standard therapy drug, and the market leader drug often are not synonymous, especially in different regions. While regulators may request a comparison to the current or gold standard, the comparison to all three can be important, especially from patient and health care provider perspectives because that will eventually be the choice they will have to make.  

 Figure 1. The pharmaceutical R&D process. Courtesy of the European Federation of Pharmaceutical R&D Process.  

There are two reasons to consider Phase IIIb studies: they are done either at the request of agencies, or are driven by the needs of the industry. When a regulatory agency deems that a product can be brought to market even though some information is mis-sing from the paperwork, a conditional approval is given along with a request for additional data. It is good to remember that additional information can be requested by the agency with any new license. That request can be a follow-up measure communicated at the time of approval, and can include data from the preclinical or clinical area, pharmacovigilance data, better outcomes data, etc. 

Yet an "approval under exceptional circumstances" can be granted in cases where there is an unmet medical need in a well-defined population, and can be granted with less than fully comprehensive datasets. The approval process typically is accelerated, but still leads to specific obligations that the Market Authorization holder needs to fulfill in order to keep the license. Both specific obligations and follow-up measures are postapproval commitments that are usually conducted as Phase IIIb trials. A restricted license usually becomes unrestricted upon fulfillment of these commitments.

Companies too may define a need for data above what is needed to obtain a license, and this constitutes the second set of drivers for Phase IIIb studies. Common drivers include a better understanding of the benefit/risk balance, data in specific subpopulations (e.g., children and the elderly), identification of less common adverse reactions, refined dosing recommendations, comparison of the new product to the current medical/gold/ market-leader standard, or trials for indications for which use of the drug is presumed once available.  

Well-planned studies designed to pinpoint additional data are increasingly important as a result of the EU's emphasis on added therapeutic value.

Applied Clinical Trials-08-01-2004

Sex and Race in Clinical Trials

EU Climate: Pharma Health Is at the Patient's Expense

Not at Your Service

Letters to the Editor

Japanese R&D: Branching Out

Achieving Regulatory Success in Phases IIIb and IV

Project Management Platform in an Academic Environment: The EORTC'S Promising Experience

A Closing Thought: Prescribing Fixes for a Broken System