Like other major business sectors, the pharmaceutical industry is under constant scrutiny regarding the way it operates. Since there is an ever-continuing rise in interest by the media and public in the type of health care service being offered, pharmaceutical companies cannot avoid being caught up in the discussion of such issues. Medicines produced by the pharmaceutical industry are a key part of the delivery of an effective health service. Media coverage of the pharmaceutical industry's activities has often been negative, and whether they like it or not companies have to pay greater attention to their public image.

Public perception cannot be ignored, particularly since health care is a major election issue and voter opinion will have an impact on a government's policies. For example, in 2002 the U.S. seniors group AARP accused some pharmaceutical companies of using "front" groups that purported to represent the elderly and released messages that favored the industry's point of view on issues such as pricing.

  These types of claims often result in major press coverage and can be highly damaging to the pharma industry. This is particularly unfortunate, since such publicity overshadows the pharmaceutical industry's vital role in researching and developing medicines.

As the pharmaceutical industry runs clinical trials to develop its products, it must engage the public and show them that it is working in their best interests. Otherwise, they will not volunteer to participate in trials, which will effectively hamper the development of new medicines.

In recent years, the concept of corporate social responsibility (CSR) has grown in importance. CSR is often discussed at the highest levels within companies, but there are a variety of interpretations as to what it means.

Issues such as respect for employees, environmental responsibilities, relationships with local communities, and fair trade with developing nations often feature as part of CSR.

  In truth, it is probably impossible to find a strict definition that suits all companies and their activities. CSR can be subjective, relying on interpretations of how commercial activities are perceived in terms of integrity, fairness, and respect for individuals.

As a business operates to generate profit, those advocating CSR are essentially asking companies to look beyond how their decision-making impacts on commercial activities and examine the effect on the society around them. This is no easy task, since an activity that generates money for the company could actually be perceived negatively in the strict context of CSR. 

Interestingly, the economist Milton Friedman believed that CSR was misguided, as the only responsibility of a business was to generate profit.

  However, this point of view is easily countered, since businesses depend on the society that surrounds them and their staff is influenced by what takes place outside their company's boundaries. Company staff members are also consumers who, like other patients, seek affordable medicines for themselves and their families. Furthermore, they will have concern for global issues such as improving health care in the developing world.

Recently, health care charities, pharmaceutical companies, and international not-for-profit organizations jointly signed an open letter to the G8 leaders calling for them to address health care issues affecting developing countries and provide incentives for the private and public sectors to work together in resolving the situation.

  Thus, those working in pharmaceutical companies should not have great problems identifying issues that are considered important by the public. 

Staff turnover in the pharmaceutical industry can be high, and if a company wants to retain talented people it must pay greater attention to the conditions in which they work. Replacing an experienced staff member is no easy task, and one company's loss can be another's gain. For example, when large pharmaceutical companies have down-sized, smaller biotech companies have often benefited from taking on the experienced people who suddenly found themselves in the job market. In many cases these individuals have thrived, as they have been able to apply their knowledge in an atmosphere free from bureaucracy.  

The term "human capital" has often been used as a means to assign value to staff within an organization, but although many senior managers can discuss such a concept, few are able to demonstrate to their staff that their work is truly appreciated. In fact, paying greater attention to staff value can be a huge asset to companies, as the best candidates in the job market will be attracted to work for a dynamic organization that takes care of its employees. Staff turnover can also be reduced because people feel as if they're part of a cohesive team.  

This process can be enhanced if a company has recognized CSR credentials, as staff members and job-seekers alike will view a company with credentials as standing out from competitors because of how it views its role in society. After all, they are themselves drawn from society and will be concerned about the same global issues as the general public. 

For example, the U.S. biotech company Genentech has won several corporate awards, which are undoubtedly an attraction for those seeking to work in the health care sector. Many of these awards are based on employee responses to independent surveys that focus on work conditions and external analyses of the corporate culture. In 2005, for the seventh consecutive year 

 magazine named Genentech one of the "100 Best Companies to Work For," and in 2004 it was named No. 1 Employer by 

  The company's image is enhanced even further by the fact that in spring 2005 Genentech was voted Top Corporate Citizen by 

 included it in their third annual list of corporate philanthropists in the Bay Area.

CSR is unavoidable in the modern business world, and the concept should be embraced rather than feared. The pharmaceutical industry has nothing to gain from the public taking a negative view of its activities, but everything to gain from demonstrating to them that companies are an essential part of health care. Without the pharmaceutical industry and the commercial forces that it harnesses in R&D, many drugs would not reach the market—but this is rarely discussed by the media. Equally, companies must look beyond commercial decisions and openly address the issue of affordability, as governments are increasingly shifting health care costs to patients. They must also demonstrate their commitment to staff if they wish to harness their talents over the long period required to develop new drugs. 

  budgets, proposals and marketing executive, Chiltern International, 

www.inpharm.com/External/InpH/1,2580,1-3-0-0-inp_intelligence_art-0-287636,00.html

2. R. Moynihan, "US Seniors Group Attacks Pharmaceutical Industry 'Fronts,'" 

bmj.bmjjournals.com/cgi/content/full/326/7385/351

3. F. Kermani and P. Bonacossa, "New Ways to Recruit Trial Subjects," 

www.actmagazine.com/appliedclinicaltrials/article/articleDetail.jsp?id=80333

4. T. Donaldson, "Defining the Value of Doing Good Business," 

news.ft.com/cms/s/748f21be-d377-11d9-ad4b-00000e2511c8,dwp_uuid=1d0ff528-c86c-11d9-87c9-00000e2511c8.html

5. Open Letter to the Leaders of the G-8 Nations, The Global Alliance for Vaccines and Immunization, 17 June 2005, http://

www.vaccinealliance.org/resources/PPPletter_17Jun2005.pdf

6. Awards & Recognition, Genentech, 2005, http://

www.genentech.com/gene/about/corporate/awards/index.jsp

Articles

Guest Commentary

CSR is in the best interest of the public at large...and the pharmaceutical company itself.

Why Corporate Social Responsibility Makes Sense

It has been well over a year since the new legislation on clinical research was introduced across the 25 states in the European Union (EU).

  It was indeed timely to standardize research practice in both the commercial and noncommercial sectors, but concerns have since been raised on the new administrative, legal, and financial responsibilities facing sponsors of independent noncommercial clinical trials.

In this paper, we will provide a short appraisal of the need for this kind of research, describe the present environment, and discuss some perspectives for clinical researchers wishing to conduct postregistration medicinal noncommercial trials. 

Typically, when pharmaceutical companies test their compounds they choose the most favorable setting (e.g., in selected populations with fewer co-existing conditions). Trials may use surrogate clinical endpoints instead of more relevant endpoints. Market pressure and the narrow agenda for development of drugs often leave many important issues unresolved, requiring further evaluation in "real life" settings more relevant to clinical practice. 

Independent noncommercial research fulfills the need for large-scale, long-term, subject-focused trials, comparing viable alternative clinical strategies and addressing physiopathological issues. Data from such trials may also be useful to health policymakers and assist them in deciding on the appropriate use of limited financial resources in both resource-rich and resource-poor settings.

For noncommercial investigators, the most challenging result of the new environment is the concept of "sponsor." Now, all interventional research (i.e., where patients are assigned to particular therapeutic strategies by a trial protocol) must be conducted with a sponsor, defined in the EU Clinical Trial Directive as "an individual, company, institution or organization which takes responsibility for the initiation, management and/or financing of a clinical trial." This means increased responsibility for all sponsors, in both commercial and noncommercial research.

It is only since May 2004, with the obligation to register all clinical trials with Eudract, that the European and national authorities have known exactly what research is being conducted and by whom. What can be said is that most noncommercial clinical research is carried out at university (or affiliated) centers. These centers have expertise and know-how in the conduct of clinical trials because they work with both commercial and noncommercial sponsors. 

Single investigators or investigator groups coordinate some multicenter, multinational noncommercial trials; although when it comes to large-scale multicenter, multinational trials, these are now often coordinated by nonprofit research organizations. In practice, this simply means that the research centers provide the study participants and data, and the research organizations offer regulatory, monitoring, and funding support. Both parties provide scientific expertise. Examples of such research organizations include CHIP (Copenhagen HIV Program) and the EORTC (European Organisation for Research and Treatment of Cancer). 

It is an irony, however, that those investigators who participate in noncommercial research coordinated by research organizations are largely academics. This underlines the present day financial and structural confines of academia. Indeed, anyone reading recent European medical literature will notice the increase in discussion and debate on the problems of academic medicine and research.

  In essence, due to economic considerations, academia is now subject to the practical pressures of day-to-day clinical practice and budgeting, to the detriment of noncommercial clinical research. 

Since 2004, any idea for a noncommercial clinical trial must be tempered by very serious consideration of the new legislative environment by the investigator/sponsor. This person/organization must have resources for the scientific, ethical, regulatory, statistical, administrative, and infrastructural obligations of present day clinical trials.

The EU health research budget for 2006–2013 will be €8.5 billion ($10 billion U.S.)—more than double the present budget—for a total EU population of 454 million. This must be divided between preclinical and clinical research, and part of the budget allocated to clinical research will be necessary to facilitate implementation of the new legislation. By comparison, the U.S. National Institutes of Health (NIH) has an annual budget of $28 billion (€23 billion) for its 300 million persons. Even with this increased budget, Europe still lags behind the United States and Japan in research spending. 

So, from the perspective of the individual clinical investigator or group of investigators, what are the options for performing a clinical trial of scientific interest in the new legislative environment? They may apply for academic grants, request European or national funding, or seek research charity support—all of which impose substantial administrative and accountability constraints. An easy option would be to approach a pharmaceutical company. This would indeed be a tempting facility involving a minimum of administrative hassle, certainly much less than any grant application to national or EU authorities or even their academic institutions. Investigators, academic institution governors, and research organizations should, however, always be mindful of intellectual property protection, freedom of publication, and upholding patient/public confidence in clinical research practice.

And what about the financing of the clinical centers?  Indeed, the sorry situation is that because there is no system of recognition for centers in which noncommercial research is conducted, they receive no dedicated funding from any source for this specific activity. 

There have been thoughtful papers in recent medical literature on the need for financial means and the political will for the support of noncommercial research and for the creation of a central European agency that would promote, coordinate, and allocate funding.

  We can only endorse the appeals of these authors. 

Our emphasis for the future will be on investigators and research centers. It is they who are at the center of this type of research. There is no doubt about it: Noncommercial research in Europe is in a difficult situation. Academics and clinical researchers were not adequately consulted on the 2004 legislation, and did not therefore work toward more facilities for this type of research. Clearly, the days of a "soft" approach to noncommercial research in Europe are gone. We are now in a highly professional, single system on par with the pharmaceutical industry. 

Noncommercial research is little known and undervalued.  In our view, it is primarily the responsibility of clinical investigators—who are, after all, the primary advocates for this type of work—to use the popular press (in all its forms) to inform and shore up support from a largely ignorant public and their political representatives. 

And within the investigative centers, there must be awareness and training of personnel at all levels to permit growth and survival of 21st century noncommercial clinical research. 

At national levels, positive acknowledgment should be given to recognized centers conducting this type of research through the provision of dedicated funding, with periodic evaluation of the quality of research practice and the quantity of scientific production of such centers. 

It has been suggested that investigators organize themselves into networks of centers of research for each pathology.

  Indeed, some dynamic networks already exist for the major pathologies (i.e., HIV, cancer, cardiology). These networks would be investigator-driven and, with adequate funding, free from political and commercial influence. 

Ongoing intensive research into the clinical applications of proteomic and genomic advances in medicine will have benefits in the long term for all clinical research. These are still in the early stages of evaluation, but the potential for individualizing patient therapy is enormous.

  A more targeted selection of participants for clinical trials will mean that in the future there will not be a need for such large numbers, as seen in some of today's mega-sized trials, thus lowering infrastructural and operational costs.

  This, however, is some time in the future. In the meantime, researchers must invest commitment and energy in adapting to their present environment. 

Wider access should be granted to the Eudract database. At present, this is only accessible to each sponsor for information on their own trials—done in order to protect the interests of the commercial sponsors. Those noncommercial trials using approved medications have only scientific or participant welfare considerations, so access to Eudract would avoid duplication and waste of scarce financial resources. 

Noncommercial research is in a weak situation in Europe. It is clearly dependent on the dynamism of the clinical investigators themselves in a setting that will need heavy financial and infrastructural support in times to come. 

 RN, is a research nurse and site coordinator and 

 MD, PhD, is the head of department, The Department of Infectious Diseases (PL5), St. Pierre University Hospital, 290, Rue Haute, 1000 Brussels, Belgium, +32 2 535 41 31, fax +32 2 539 36 14, email: 

*To whom all correspondence should be sent.

 1. Guidelines for Good Clinical Practice, 

www.ich.org/MediaServer.jser?@_ID=482&@_MODE=GLB

 2. Directive 2001/20/EC of the European Parliament and the Council of 4 April 2001 on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, 

 3. Detailed guidance on the European Clinical Trials Database (Eudract Database), http://

pharmacos.eudra.org/F2/pharmacos/dir200120ec.htm

 4. Detailed guidance on the European Database of Suspected Unexpected Serious Adverse Reactions (Eudravigilance–Clinical Trial Module), http://

 5. Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical trial of medicinal products for human use, http://

 6. Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments, and declaration of the end of the trial, http://

 7. Detailed guidance on the collection, verification, and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use, http://

 8. A. Hemminki, P. Kellokumpu-Lehtinen, "Harmful Impact of EU Clinical Trials Directive," 

 9. A.H. Morice, "The Death of Academic Clinical Trials," 

10. Editorial, "Who's Afraid of the European Clinical Trials Directive?" 

11. F. Meunier and D. Lacombe, "European Organisation for Research and Treatment of Cancer's Point of View," 

12. S.R. Tunis, D.B. Stryer, C.M. Clancy, "Practical Clinical Trials. Increasing the Value of Clinical Research for Decision Making in Clinical and Health Policy," 

13. E. O'Doherty and N. Clumeck, "The EU Directive: Practical Implications for Clinical Research Teams," 

14. P. Tugwell, "Campaign to Revitalise Academic Medicine Kicks Off," 

15. Editorial, "Who Cares About Academic Medicine?" 

Feature Article

New EU legislation heralds a difficult funding environment for nonprofit research centers.

Challenging Times for Noncommercial Researchers

Is it true that there is not enough demand for a rigorous participant protection oversight program as PHRP (Partnership for Human Research Protection) suggested in September 2005 when it announced that it was going out of business with 10 organizations accredited? That is not what we found. 

AAHRPP (Association for the Accreditation of Human Research Protection Programs) has seen demand by research organizations and sponsors grow. Hundreds of organizations have come to AAHRPP to put their participant protection programs to the test by submitting to an objective assessment of whether they have integrated safeguards at every level of their research operations. 

Accreditation is an outside measure of the quality and reliability of a research organization's program for participant protection, and sponsors have found that the quality also shows in the research itself. Sponsors and regulators know organizations that are rigorous in the application of their participant protections are equally committed to solid, credible, reliable research. 

			 According to Marianne Vanderwel, associate director, corporate pharmaceutical regulatory monitoring, Pfizer Canada, "Accreditation helps industry by improving regulatory compliance through promoting a culture of responsible conduct of research by competent investigators." 			

Since AAHRPP's founding we have accredited 35 organizations, including 102 research entities. Another 360 are in the process of accreditation. We expect that within the next two to three years all the major research intensive organizations will have completed the accreditation process and that many other research organizations will be volunteering their participant protection programs for close scrutiny, including clinical research organizations, government agencies, hospitals, independent IRBs, research sites, and universities. 

Accreditation builds trust and serves as a badge of honor for a research organization. Its numerous tangible advantages not only benefit the institution, but also the research participants, sponsors, and government regulators. 

Going through the process significantly improves an organization's participant safeguards. Organizations carefully examine their programs and measure them against objective national standards that go beyond the federal requirements. Even the best programs find areas they can improve. The accreditation process helps ensure written policies and procedures clearly explain the human research protection program.  

Accredited organizations also discover organizational and budgetary benefits. As a result of the process, a number of organizations have streamlined their operations, improved collaboration and staff utilization, and saved on liability insurance through Lloyd's of London, which offers a 5% premium discount to AAHRPP-accredited research organizations in recognition of their reduced risk. 

A growing number of sponsors and regulators are recognizing that accredited organizations are more likely to be compliant. This decreases the workload for sponsors, who must demonstrate their commitment to participant protections, and regulators. 

While the FDA and OHRP have spoken in favor of accreditation, an important signal of government support is the lead many of the federal agencies have taken in seeking accreditation of their intramural research programs, including a mandatory requirement for accreditation by the VA. 

Some suggest only the leaders in the research community are stepping up while others won't submit their programs unless regulators and sponsors demand it. Although such a demand would certainly accelerate the process, the movement is already well underway. More organizations will seek accreditation because it is the smart thing to do and because they see that sponsors are increasingly making accredited institutions their first choice. When they demonstrate that their protection programs meet the test, the sponsors will have a pool of reliable research organizations from which to choose. 

Sponsors can expand that pool of superiorly qualified research organizations faster if they all make clear their preference for accreditation.  

, PhD, executive director, Association for the  Accreditation of Human Research Protection Programs, Inc.

A Closing Thought

A growing number of sponsors and regulators are recognizing that accredited organizations are more likely to be compliant.

A Consensus for Accreditation

The choice of a valid primary endpoint is crucial for a randomized controlled trial (RCT) designed to demonstrate efficacy of a new pharmaceutical drug. Recent improvements in medical management, however, have led to a continuous decline in mortality and morbidity for several common disorders, i.e., also in the incidence of clinically relevant outcomes that may be addressed in a drug trial as an endpoint. For example, secondary prevention after myocardial infarction with aspirin,  β-blockers, ACE inhibitors, and statins has remarkably lowered the rate of a subsequent cardiovascular event,

  and combination antiretroviral therapy for HIV infection has made mortality even unfeasible as a clinical endpoint.

Moreover, for many diseases a standard of care has been established, and it is often not possible anymore to compare new therapeutic options with no treatment or placebo for ethical reasons.

  As a consequence, the effect sizes observed with add-on treatments when compared to standard treatment are generally lower today. Both the reduced incidence of disease-related events and the limited chance to provide significant differences in treatment effects require trials with large sample sizes.

As a solution to maintain feasibility of RCTs, particularly those facing low event rates, the investigation of composite endpoints has been introduced and become fashionable in the last few years. 

A composite endpoint in a RCT consists of multiple single endpoints that are combined in order to confront an investigational drug with a higher number of events expected during the trial. For instance, the primary composite endpoint may include mortality along with nonfatal endpoints such as hospitalization and cardiac arrest in chronic heart failure patients,

  or along with myocardial infarction and stroke in hypertensives.

 The major advantages in using a composite endpoint are: statistical precision and efficiency will be increased

 ; trials become smaller, less costly; and the results of promising new treatments will be available earlier. If more than one outcome is important for efficacy evaluation, a composite endpoint can efficiently deal with the issue of multiplicity.

  A summary measure for drug efficacy can be defined

  (e.g., the assessment of skeletal-related events [SREs] in trials for prevention or treatment of bone metastases). 

The selection of composite endpoints has been regarded as "a useful strategy" for registration of pharmaceuticals in the ICH E9 guideline.

  A Points-to-consider document released by the European Agency for the Evaluation of Medicinal Products (EMEA) specifies regulatory requirements.

The use of a composite endpoint in a clinical trial is usually justified if the following assumptions are respected: 					

The individual components of the composite are clinically meaningful and of similar importance to the patient.

The expected effects on each component are similar, based on biological plausibility

  (which is, in the end, the rationale for using a composite endpoint). Accordingly, regulatory guidelines also require components for which it can be assumed treatment will beneficially influence in a similar way.

The clinically more important components of composite endpoints should at least not be affected negatively.

As a consequence of the third assumption, regulatory authorities require all components of a composite endpoint to be analyzed separately.

  One needs to be aware whether a treatment affects all components or just a single outcome.

The selected individual components of a composite endpoint, as reported in the biomedical literature, are not always clinically meaningful. The suitability of a combination of all-cause mortality, the need for intubation and mechanical ventilation together with intensification of steroid therapy in a trial of patients with chronic obstructive lung disease

  may be questioned, as patients are likely to consider the need for steroids of trivial importance.

Moreover, the problems with nonvalidated surrogate endpoints need to be kept in mind when selecting outcome variables for the composite, particularly when a relationship between the surrogate and mortality has not been established. Although strongly effective in suppressing ventricular arrhythmia, class IC anti-arrhythmic agents were shown to significantly increase mortality after myocardial infarction.

  In contrast, carvedilol treatment demonstrated favorable effects on survival in patients with moderate to severe heart failure; however, there was little benefit on exercise tolerance or quality-of-life scores.

If a composite endpoint consists of death, myocardial infarction, and stroke, for example, the distribution of these single outcomes is of lower importance. The situation may be different if the less important outcomes account for the majority of events. This is particularly the case when "soft" clinical endpoints like refractory angina or the associated need for revascularization are combined with the risk for death or myocardial infarction. 

  for instance, compared invasive and medical treatment in an elderly population with chronic angina. The frequency of the composite endpoint (death, nonfatal myocardial infarction, and hospital admission for ACS) was much lower with revascularization; however, this was due to a marked difference in hospital admissions, which accounted for 75% of the events in the medical treatment group. In contrast, there were twice as many deaths in the invasive treatment group. The question remains how to interpret the results and inform a patient who has to decide between conservative or surgical therapy.

The Irbesartan Diabetic Nephropathy Trial

  compared the renoprotective effect of the angiotensin blocker irbesartan with amlodipine in type 2 diabetics with nephropathy. The primary composite outcome consisted of all-cause mortality, end-stage renal disease (ESRD), and doubling of the serum creatinine concentration. In the definition of ESRD, the serum creatinine concentration (increase > 6.0 mg/dl) was one component. The authors did not mention how ESRD diagnosis was assessed according to the underlying definitions; a significant contribution of creatinine values to ESRD diagnosis can not be excluded, which would mean that a laboratory value had determined two of the three components of the composite. 

But even independent of this, the majority of events concerned doubling of the serum creatinine concentration and were the main basis for the overall beneficial effect of irbesartan compared to amlodipin. Reduction of ESRD with irbesartan failed to be statistically significant (when adjusted for blood pressure), and mortality—the most important endpoint—was not different between both treatment groups. The question remains: What at all is the value of serum enzyme concentrations as part of a composite endpoint, particularly if the risk of death is unchanged in the investigated population? 

Adding a component that foreseeably is insensitive to treatment increases variability and, as a direct consequence, makes it more difficult to provide clear results, particularly for interpreting noninferiority trials.

  Time-to-treatment failure is therefore seldom useful for regulatory purposes, as treatment discontinuation because of toxicity or voluntary withdrawal has no direct relevance to the underlying disease process or the effectiveness of a therapy.

One needs to be aware that several drugs (or new indications, respectively) have been approved based on composite endpoints although evidence of mortality reduction was lacking. As an example, glycoprotein IIb/IIIa inhibitors have shown to significantly reduce a composite outcome of death, myocardial infarction, or refractory angina; however, all-cause mortality, the most important component, was not changed.

To assess the real clinical value of a drug, it is necessary to look in detail at the wording of the approved indication and the effects on single, clinically relevant endpoints. According to the systematic review by N. Freemantle et al.,

  more than one third of published trials using a primary composite outcome with a mortality component showed an overall significant result, although the single mortality endpoint did not. 

Finally, one should be aware of a potential bias. There may be competing risks between endpoints, and one needs to particularly look whether a positive composite endpoint camouflages a negative individual outcome or dilutes the effect of the treatment on mortality. Myocardial infarctions or hospitalizations may be reduced by a treatment only because mortality is increased. Studying nonfatal events without including deaths is methodologically invalid, as those with the worst outcome are censored.

  Endpoints that require subjective judgement (e.g., ECG findings or X-rays) are also subject to bias. Therefore, it is important to standardize endpoint assessment, preferably by a blinded endpoint adjudication committee, as recommended by an EMEA guideline.

The following example demonstrates how important an endpoint committee may be. In the so-called TRIM trial, the endpoint committee reduced the number of patients with the endpoint myocardial infarction or refractory angina by 13.6% and reclassified study-related events for 28% of the patients.

There is no guarantee for success when using a composite endpoint. Despite an underlying biologic rationale, the effects on each component of the composite endpoint may be unexpectedly different, as shown in the LIFE trial

 : compared to atenolol, losartan significantly reduced the incidence of stroke, but, on the other hand, it increased the incidence of myocardial infarction. 

A "worst case scenario" happened in the CAPRICORN trial,

  which investigated carvedilol in patients with left-ventricular dysfunction after myocardial infarction. The original endpoint, all-cause mortality, was changed during the trial to a new composite consisting of mortality and hospital admissions. Whereas the "old" endpoint achieved a p-value of 0.03, the "new" combined endpoint, in contrast, failed to show statistical significance. 

A further problem may arise if the decision to stop a trial early is based on the monitoring of a composite endpoint, particularly if this is driven by the least patient-important outcome.

  Such an approach may lead to overestimation of the benefit and underestimation of the risk. 

The use of a composite endpoint in a clinical trial is comprised of chances and risks. Composite endpoints can be of value if both requirements and limitations are respected. When planning a trial or reading about a trial with a composite endpoint, the following key questions should be answered:  					

Does the composite endpoint really measure a disease?

Does the use of a composite endpoint solve a medical problem or is it just for statistical convenience?

Are the individual components of the composite endpoint valid, biologically plausible, and of importance for patients?

Are the results clear and clinically meaningful? Do they provide a basis for therapeutic decisions? Does each single endpoint support the overall result?

And a last word addressed to journal editors: Trials with composite endpoints should be reported unequivocally, providing all information necessary for judgement of the trial. 

 MD, FFPM, a Swiss specialist in pharmaceutical medicine, is medical director with PFC Pharma Focus AG, Chriesbaumstrasse 2, CH-8604 Volketswil, Switzerland, email: 

 1. S. Orn and K. Dickstein, "Pharmacotherapy Following Myocardial Infarction—A Review of Current Treatment Practices," 

 2. F.J. Palella, K.M. Delaney, A.C. Moorman et al., "Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection," 

 3. World Medical Association, "Declaration of Helsinki," 

 4. K.J. Rothman and K.B. Michels, "The Continuing Unethical Use of Placebo Controls," 

 5. M.S. Lauer and E.J. Topol, "Clinical Trials—Multiple Treatments, Multiple End Points, and Multiple Lessons," 

Journal of the American Medical Association,

 6. J.N. Cohn and G. Tognoni, for the Valsartan Heart Failure Trial Investigators, "A Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic Heart Failure," 

 7. B. Dahlöf, R.B. Devereux, S.E. Kjeldsen et al., "Cardiovascular Morbidity and Mortality in the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE): A Randomised Trial against Atenolol," 

The use of composite endpoints are being regarded as a useful strategy, but caution must be applied as there are both risks and benefits.

Composite Endpoints: Proceed with Caution

European Union ministers gave their broad backing to the proposed rules on pediatric medicines at their Social Affairs Council in March. As regular readers of this column will know, the two years of intense discussion so far on this proposal have been geared largely toward stimulating clinical research on products for children and ensuring that medicines used to treat children are appropriately authorized for use in pediatric populations. 

The council agreed with the proposal's objectives and with many of the views expressed by the European Parliament, which gave a first reading to the proposed rules last September. But it has added some changes, notably about improving research into pediatric use of off-patent medicines, keeping pediatric products on the market, and availability of information. 

"Provision should be made for research into the pediatric use of medicinal products which are not protected by a patent or supplementary protection certification," says the council—and it adds that this should be financed under EU research programs. The funding would be delivered through the EU's framework programs for research "or any other [EU] initiatives for the funding of research." 

The council has decided to insert a new article to ensure that products stay on the market if they have a pediatric indication that has benefited from the rewards in the regulation. This is in line with similar calls from the European Parliament, but goes further, notably in systemizing the possibility for interested third parties to continue marketing the product, and in imposing a deadline for informing the agency of the intention to discontinue placing a product on the market. When periods of protection have expired on a pediatric product and the marketing authorization holder intends to discontinue it, he "shall transfer the marketing authorization or allow a third party, which has declared its intention to continue to place the medicinal product in question on the market, to use the pharmaceutical, preclinical, and clinical documentation contained in the product file." To facilitate transfer, the marketing authorization holder will have to inform the agency of its intention to discontinue placing the product on the market at least six months before the discontinuation. 

The beloved EU concept of "transparency"—or what normal people call information—gets a boost from the council too. It supports the introduction of transparency into the European pediatric clinical trials register foreseen by the regulation. In order to increase the availability of information on the use of medicinal products in the pediatric population, and to avoid unnecessary repetition of studies in the pediatric population that do not add to the collective knowledge, says the council, the European database provided should include a European register of clinical trials of medicinal products for pediatric use, comprising all ongoing, prematurely terminated, and completed pediatric studies conducted both in the EU and in other countries. 

The council, however, says that clarification is needed about what is to be included and how the details would be entered. The database shall include, says the council, clinical trials carried out in non-EU countries that are contained in an agreed pediatric investigation plan, in addition to European clinical trials. For trials carried out in non-EU countries, the full details are to be entered into the database by whoever has submitted a pediatric investigation plan. 

The agency is to make public part of the information on pediatric clinical trials entered in the European database. This will include details of the results of all pediatric clinical trials submitted to the competent authorities, even when terminated prematurely. These results have to be submitted without delay to the agency by the clinical trial sponsor, the marketing authorization holder, or the recipient of the agency review of the pediatric investigation plan. 

But the council diverges from the European Parliament on how to treat ongoing trials. The parliament wants to open the possibility to provide information on pediatric studies still underway. The council says this is not necessary, and points out that the proposal does not require the completion of all pediatric studies at the time of application for marketing authorization: There is a "deferral" provision that allows for delay in the initiation of pediatric clinical studies so as to ensure that the studies are only done when it is safe and ethical to do so.  

A deadline should be set for the submission of a pediatric investigation plan, believes the council, in order to ensure early dialogue between the sponsor and the pediatric committee on whether studies are required and, if so, the type of studies and their timing compared to studies in adults. It is, however, a deadline only to submit a draft plan—not a deadline for the initiation of studies. In addition, the plan may contain a request for a deferral of the initiation or completion of studies. 

The pediatric investigation plan may subsequently be monitored, and the council considers this valuable as a mechanism for ensuring continuing dialogue between the applicant and the pediatric committee during product development. Trying to force early pediatric studies of a product—as the parliament is suggesting—could backfire and impede innovation in pediatric therapeutics, with negative consequences for public health, the council believes. 

Legally speaking, it is impossible for pediatric studies completed prior to the entry into force of the new rules to be included in the pediatric investigation plan. But so as not to discourage current research, existing and ongoing studies at the time of its entry into force will be eligible for inclusion once the regulation is adopted. 

Members of the pediatric committee do not need to have international-level experience and knowledge of the pharmaceutical industry, says the council, but—unlike the European Parliament—it does not consider the committee to be primarily responsible for the ethical assessment of the pediatric investigation plan. 

The European Commission, which proposed the new rules in 2004, is happy with the council's position, and to finalize the process, the European Parliament now has to give the draft a second reading—probably this summer. 

But it has not all been plain sailing—and choppy water may still lie ahead. At the March council meeting, Poland voted against the position that the other 24 member states shared. It said that like its council colleagues, it was in favor of measures to promote the development of research into medicines for children, and to provide the pediatric population with medicinal products that are safe and effective. But it felt the incentives offered were too generous, and the opportunities for generic copies were too restricted. Thus, it rejected the proposed extension of protection periods for original products, "since it delays the marketing of cheaper generic products, thereby restricting patients' access to pharmacotherapy and increasing expenditure in national health care budgets. Poland considers that this conflicts with the overriding aim of this regulation." 

And an improbable pairing of Latvia and Belgium expressed similar reservations, without actually voting against the proposal. A system of rewards and incentives is necessary to achieve the objective, but these "should be commensurable with the costs incurred by manufacturers and result in the lowest possible impact on the state budget and patients."  

While the pediatric rules are still making their way through the EU legislative pipeline, the final version of the new rules on conditional marketing authorizations for medicines appeared in March. These formalize arrangements for bypassing the normal preauthorization procedures. "To meet unmet medical needs of patients and in the interests of public health, it may be necessary to grant marketing authorizations on the basis of less complete data than is normally the case and subject to specific obligations," says the new rule.  

These conditional marketing authorizations will be granted only where the clinical part of the application dossier is less complete than normal. But clinical trial staff need not fear that they are to be rendered redundant by conditional marketing authorizations. The new rules make clear that although the data upon which an opinion on a conditional marketing authorization is based may be less complete, the risk–benefit balance should be positive, and the benefits of making the product immediately available should outweigh the risk inherent in the fact that additional data are still required. 

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.

View from Brussels

EU Council supports pediatric medicines proposal, but adds some changes.

Another Step Toward EU Pediatric Trials

Secure, Web-based product warehouses patient health data across multiple sites

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 DB*FOCUS tracks all activity into and out of the patient record, either at a single location or across multiple sites. In this case, patient data are multi-encountered and longitudinally linked across all facilities in the clinical study. The security feature offered by the product enhances privacy compliance, including HIPAA.  

According to Convergence CT, DB*FOCUS can save costs because its easy installation eliminates the need for a full-time database administrator, plus it also reduces organizational inefficiencies and optimizes resource utilization.  

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The device uses sensor grid technology and a proprietary process of printed conductive inks to form a smart label that automatically tracks whether or not a patient takes medication. Med-ic ECM records the time each pill is expelled from the blister package, creating a record for analysis by clinical trial monitors.  

The device's Med-ic ECM CertiScan RF Reader and CertiScan Compliance Monitoring Software capture and display patient compliance data with the latest RFID technology. The compliance monitoring system is disposable and features the technical controls to support 21 CFR Part 11 compliance without active input by the trial monitor.  

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Software delivers seamless supply chain management that integrates with third-party systems   

(New Castle, DE) has found a way to help clinical supply professionals carry out all of their critical tasks with the click of a mouse. Version 3.2 of its ClinChain Plenish software package is a fully validated, 21 CFR Part 11-compliant software system that enables material receipts, manufacturing and primary and secondary packaging requests, site distributions, drug returns, and destructions.  

At the heart of ClinChain Plenish are sophisticated data inheritance rules and inter-related drop-down menus that minimize user input and preserve data integrity. The software includes enterprise features such as multi-user client/server architecture, a robust reporting tool, broad genealogy tracking, and flexible data querying capabilities. It also integrates with other databases and third-party software standardized databases.    

eShowcase

The Food and Drug Administration unveiled its long-awaited Critical Path Opportunities List in March, a summary of some 76 scientific projects that agency leaders believe can increase the efficiency, predictability, and productivity of medical product research and development. At the top of the list are a number of initiatives to identify and validate new biomarkers for clinical studies and product evaluation, along with proposals to improve clinical research practices and trial design. New statistical and computational approaches may make clinical research more informative, while computer modeling promises to avoid wasted efforts and streamline development programs. 

FDA believes that new analytical and diagnostic technologies open the door to developing more accurate and predictive measures of how a test product may affect physiological or pharmacological responses. In vitro diagnostic tests could identify patients at risk for adverse events as well as those most likely to benefit from therapy. New safety biomarkers may provide early indications of a compound's toxicity and avoid wasted research efforts. And markers of drug metabolism may accelerate individualized drug dosage that can yield safer and more effective treatments. 

As the most expensive aspect of drug development, a main Critical Path objective is to encourage more productive research practices. This involves moving away from long and costly empirical testing and adopting trial designs based on a better understanding of underlying disease states and drug mechanisms of action. FDA wants sponsors to conduct more "learning trials" to explore dose–response relationships and yield more information about product performance. Instead of just gathering data on how a population responds to a test product, the aim is to gain information on how variations in disease states, organ systems, and genomes can make individuals respond differently to treatment. 

The list of proposals for creating more efficient clinical trials ranges from fairly practical approaches, such as establishing common standards for case report forms and for collecting clinical trial data, to devising more sophisticated research models. FDA would like to see consortiums formed to clarify statistical methods and propose standards for designing non-inferiority trials and studies with enriched patient populations. Agreement is sought on rules for revising trials based on interim results and for using historical data and animal studies to better predict human response. Groups also could address how to handle studies compromised by subject attrition and missing data. 

Another important objective is to develop study protocols tailored to specific diseases or conditions. New trial designs could improve understanding of how treatment response relates to outcomes for cancer patients. More analysis on whether pathogen levels in the blood accurately correlate to infection may improve development of vaccines and antibiotics. Standardized measures of patient symptoms and pain scores would help researchers measure a variety of indicators. 

The much anticipated list features initiatives in biomarkers and research productivity.