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TRIAL DESIGN : Global Pediatric Research Update  Prepare for the Seasonal Diseases That Can Derail Your Trial  Also in this issue : EMEA Reorganizes, New FDA Team Eager for 2010, Unnecessary Clinical Data, Cardiac Safety: Consider Centralization

Applied Clinical Trials Digital Edition - January 2010

						The former Vice President and Global Head of Quintiles eSolutions Business, 

, has now taken on the role of Head of Business Development for 

As the new General Manager of Pharmaceuticals for 

 will gain the responsibilities for sales and future expansion into Europe of the company's pharma businesses. 

With 25 years of successful sales and sales management experience, 

, as its new worldwide Executive Director, who will direct DIA's global operations and strategic expansion. 

 has been promoted to Director of Program Management, and 

, with the company since 2008, was promoted to Senior Director of Business Development. 

 (Munich, Germany) as a principal Consultant. 

 as Executive Vice President of Worldwide Sales.      

A multiyear agreement will put into effect the plans for 

 (Budapest, Hungary) to adopt and implement 

To provide sponsors with research and technology services for faster evaluations of treatment side effects, 

 (Kansas City, MO) have entered into an agreement.

 (New York, NY) announced a multiyear contract with 

 (New York, NY) for use of Medidata Grants Manager. 	

 (Yardley, PA) as one of the "Best Places to Work in PA" for 2009.

 (Waltham, MA) has won the 2009 Society for Clinical Data Management (SCDM) Data Driven Innovation Award competition for a joint project with customer Merck & Co.

Recognizing the company's therapeutic concept for the treatment of distinct orphan diseases, 

 (Appenzell, Switzerland) received the award for "European Orphan Diseases Entrepreneurial Company."

In acknowledgement of its contributions to medical communications, 

 (Flemington, NJ) is the 2009 recipient of the American Medical Writers Association's "Harold Swanberg Distinguished Service Award."

 (Philadelphia, PA) was honored with the award for Best New Product for its ePRO based suicidality monitoring solution at the 2009 European Outsourcing Awards.

 (Boston, MA) has officially been launched.

 (Wilmington, NC) has changed its name to 

As part of the reform of the health care system by the U.S. government, 

(Philadelphia, PA), attended a roundtable discussion with Governor of Massachusetts 

 to discuss how to promote widespread HIT adoption. 					

Launching resourcing services in Switzerland and Belgium, 

 (Basking Ridge, NJ) now provides personnel in over 50 countries.

To increase its presence in the North American market, 

 (Manchester, UK) will open a U.S. office in Boston, MA.

To accommodate demand in outsourcing of clinical supply management services,

(Craigavon, Northern Ireland) has completed a 67,000 square foot expansion to its North Carolina facility. 

 (Doylestown, PA) has released GenSight version 8.0., with features to further facilitate enterprise-wide portfolio management.

 (Waltham, MA) presents the newest version of open source electronic data capture (EDC) software for clinical trials. 					

 (San Diego) released Sages Templates Version 1.1.3, with redesigned and extended templates.

Upgrading its software in an effort to streamline supplier collaboration, 

 (Austin, TX) has released Xtended Process Control (X.PC) 5.7dm.

 (Wayne, PA) announced the release of StartingPoint 4, offering new content templates, improved functionality, and compliance with Windows 7. 

The ERT team accepts their award for Best New Product at the 2009 European Outsourcing Awards.

Community

Industry news focusing on the people and organizations who work in the clinical trials profession.

Business and People Update January 2010

The global market in sales for oncology drugs is anticipated to expand from around $48 billion in 2008 to more than $85 billion in 2013. This is based on 2008 data from Cutting Edge Information. Currently, more than 4,700 clinical trials are in progress for oncology drugs.     

John W. Hubbard, PhD, FCP, Global President, ICON Clinical Research, had shared in an interview conducted in 2009 that ICON was seeing increased activity in the oncology space and had in fact added three more oncologists to its corporate staff in the United States. Exploring the reasons behind the increase, as well as the apparent, but not wholesale, migration of oncology trials from academia to mainstream trial venues, Hubbard noted the toxicity shift in medicines available for cancer treatment. "The older drugs were very toxic with side effects that needed to be managed," said Hubbard. "With the newer drugs, they are more targeted and the side effects aren't as bad. And there are more of them, so they are moving into a traditional drug development model." 

In fact, in a recent survey from US Oncology, 53% of the respondents felt that recruiting patients to clinical trials for targeted therapies will be less difficult than large-scale randomized trials of more traditional cytotoxic therapies. The survey respondents included a mix of oncologists (67%), and the balance clinical research professionals (33%). 

The US Oncology respondents believed that subject recruitment for clinical trials is most successful at academic medical centers (AMCs), and the reasons given in order were: better patient acceptance, large patient population/database, and more staff. 

Meanwhile, getting trials up and running remains a two-fold problem, one that AMCs may need to heed. The US Oncology survey found that regulatory red tape was the primary cause that slowed down a trial's approval. Couple that with another study from KMR Group on site contracting practices, which found site contract approval time is five to six weeks on average, but double for an oncology trial, with problems specific to start up. KMR Group attributes the lengthened oncology time to both a greater tendency for those studies to be conducted at institutional sites, which tend to take longer, and the greater complexity of oncology protocols, e.g., due to patient issues. 

Phase News

The current oncology drug development market.

Trials in Oncology only Going Up

It has been three years since the introduction of the European Pediatric Regulation,

  just one of several global initiatives focusing on children's health. The Regulation has the stated aim to protect children and improve their health through the conduct of formal clinical research in order to increase access to innovative medicines and to derive data to guide the prescriber in the use of medicines in the pediatric population.     

Similar objectives are voiced by organizations including the World Health Organization (WHO), the U.S. Food and Drug Administration (FDA), and other competent authorities who have also been trying to stimulate clinical research in children and encourage the conduct of ethical, high-quality clinical trials to facilitate the timely licensing of medicines, with relevant formulations, in order to protect children from inappropriate and often off-label use of drugs licensed for adults or from exposing children to poor quality drugs. 

Inevitably, these measures have had an impact on the pharmaceutical and biotechnology industries' research and development priorities and the international clinical trial environment. 

Most medicines given to children are used off-label.

  In hospital pediatric wards this is around 45%,

  and in the neonatal intensive care setting this can be as high as 90%. The experience gained in this way is rarely incorporated into clinical practice guidelines or medicinal product labelling. This practice, which often utilizes a simple extrapolation of dose from adult experience based on body weight or body surface area, represents a potential safety hazard by causing adverse events through overdosing, inefficacy through under dosing and the use of inappropriate formulations or substandard medicines. 

This is because children differ developmentally, psychologically, physiologically, and hormonally from adults. They also experience different health problems or disease patterns than adults. The response of children to drugs may differ for these reasons and, moreover, genetic factors will play a role in the response of a child to drugs.

In the United States, legislation in place since 1979 required pediatric data in labelling for medicinal products. Under the Best Pharmaceuticals for Children Act (BPCA),

  which was made law in 2002, an incentive of six months marketing exclusivity can be granted for products studied in response to a written request for pediatric studies, and is further supported by the Pediatric Research Equity Acts (PREA), which first appeared in 1998 as the Final Pediatric Rule, and mandates pediatric studies.

The Pediatric Regulation in Europe was preceded by the ICH Guidance 11 for conducting studies in the pediatric population.

  It also obligates pharmaceutical manufacturers to conduct clinical studies in children in accordance with an agreed Pediatric Investigational Plan (PIP) in return for six-month patent protection.  

 This global representation of the number of pediatric studies worldwide are based on 2008 numbers from "Trends in the Globalization of Clinical Research," by F. A. Theirs, in Nature Reviews Drug Discovery. 			

The Regulation is accompanied by guidance documents on various themes in pediatric research (risk management planning,

  formulations of choice for the pediatric population,

  the role of pharmacokinetics in pediatric drug development,

  and the investigation of products in the neonatal population.

There is concern that the incentives provided by the Regulation are potentially insufficient to offset the cost of developing drugs for use in children. The European Federation of Pharmaceutical Industries and Associations has voiced this concern,

  whereas generic manufacturers would prefer to have earlier access to drugs and see a shorter protection period. For marketed products, the window of opportunity is limited due to patent expiry and the cost of a pediatric development may deter companies investing in variations including new indications, formulations, and routes of administration. The House of Lords in the UK also raised the point that prolongation of the patent protection would result in increased National Health Service costs of between £30 million and £120 million per year ($50 million to $200 million) due to the higher price of branded products compared to generics.

The level of experience of clinical investigators in conducting research in children meant for regulatory submissions—in ethical and consent issues—together with a relative lack of experience of Ethical Committees in assessing pediatric trials can also impede the execution of the studies. Probably a better public awareness of the need for research in children would increase the level of parental commitment for the participation of children in trials, and a better understanding of the ethical and regulatory framework will reassure parents and carers that safeguards are in place to protect their child from unnecessary exposure to experimental drugs.  

Harmonization of the principles of clinical research (ICH) has been achieved across the three major global territories of Japan, the United States, and Europe, but pediatric regulations or provisions are not yet harmonized or even in place across all territories. 

The EMEA has contacts with main European pediatric societies and has a collaboration with the National Institutes of Health (NIH) in the United States, the WHO, the Japanese National Center for Child Health and Development (NCCHD), and existing research networks and centers and it collaborates with family/patient organizations. 

Of significance has been the establishment of a close collaboration between the EMEA and FDA involving exchange of information with respect to product-specific pediatric development, general issues in pediatric development, safety issues such as reporting of adverse drug reactions (ADR) in children, and the exchange of statistics from ADR databases. There is mutual observation of internal pediatric meetings, monthly (and as needed) teleconferences, exchange of the monthly listing of pertinent applications and EMEA/FDA decisions, and upon request exchange of final EMEA and/or FDA documents.  

Table 2: The Type of Studies Required to be Completed for PIPs 			

In Japan, the Ministry of Health, Welfare and Labor has established pediatric drug therapy review meetings in order to collect and evaluate literary evidence relating to the efficacy and safety of drug prescriptions in children. Two ordinances provide for the acceptance of pediatric data from off label use outside Japan and for an extension to the review period for medicines where pediatric studies have been performed. Since November 2009, a pediatric cluster has been developed in the Japanese Ministry of Health, Welfare and Labor to observe the monthly teleconferences between the FDA and EMEA.  

Items of Informed Consent and theLevel of Understanding of Parents			

These activities, summarized in Table 1, promise to harmonize the regulations and requirements that surround clinical studies in children from a regulatory perspective and avoid the unnecessary duplication of studies in children and unify the approach to product-specific pediatric development. 

In the United States, as of October 31, 2009, the pediatric legislation has resulted in 950 written requests (574 requests from industry and 376 issued by FDA) for 902 pediatric studies, involving more than 56,000 patients. So far studies conducted under the various regulations have recruited over 85,000 patients. Three hundred and thirty three additional labelling changes on safety, efficacy, dosing, and unique risks in children have been achieved for 156 active moieties and 163 drugs have been granted exclusivity. 

By the November 13, 2009, meeting, the Pediatric Committee (PDCO) at the EMEA reported that they had received 614 validated PIP/waiver applications covering 946 indications [see Table 2]. The majority of 66% were for products not yet authorized, 31% were for variations to an existing license, and only 3% represented off-patent products. To date, 201 positive decisions have been made on PIPs including deferrals, 120 on full waivers, and 17 negative opinions have been given. Now increasing numbers of modifications to previously agreed upon PIPs are being made with 51 modifications approved up until November 13, 2009. In PIPs approved until September 16, 2009, 520 clinical studies were required to be completed. 

The complexity of studies conducted in children has increased, with efficacy and safety studies representing 40% of all pediatric studies conducted in 2006 compared with 25% in 2000.

  Consequently, the cost to conduct clinical studies has increased, where the average cost to comply with a written request has risen from $3.93 million in 2000 to $30.82 million in 2006. The time taken to complete clinical studies in children increased as well, from 22.8 months in 2000 to 39.7 months in 2006—almost doubling.

Moreover, the economic return on clinical trials performed under the pediatric exclusivity program in the United States was variable, found to be between -$8.9 million to $507.9 million.

  Therefore, not all development programs have been offset by the rewards provided by BPCA and in the future the possible lack of return on investment may in fact deter companies from embarking on clinical research in children with new or established drugs. 

The many pediatric initiatives have had a significant impact on the pharmaceutical and biotechnology industries. In particular, pediatric development should now be provided for earlier in the development planning process and in parallel with adult development. This requires early consideration of preclinical testing, particularly in juvenile animal models, formulation development, and the acquisition of pediatric competency either within the company or through the use of external academic and specialist support such as CROs. 

Due to the unique characteristics of the pediatric population different approaches to clinical trial design are required. Adaptive designs, stratification, and cross over designs are more commonplace, and in pharmacokinetic work pharmacodynamic/pharmacokinetic modelling techniques and sparse sampling pharmacokinetic studies are often used.

  The age of the patient may dictate blood sampling limits and the use of invasive tests. Innovative techniques such as micro assays, dry blood spot, and the use of other bodily samples and noninvasive investigation techniques are often applied. 

Disease demographics, language, religion, culture, investigator–patient relationships, clinical management practices, and access to health care and medicines are all aspects of international trials that require planning in the pediatric setting. Without taking these into account, recruitment and retention may not be successful. 

There are issues in conducting clinical studies in children in emerging territories such as the accessibility to primary and secondary care and the existence of health records, which are important for eligibility confirmation and source data verification. In these regions, the existence of regulatory and ethical committee frameworks with experience in pediatric studies is not often robust. 

The competition for patients is fierce since recruitment of children into clinical studies is more difficult than for adult studies and more studies are needed. Provisions to avoid unnecessary duplication of clinical studies in children such as the collaboration between the FDA and EMEA are not yet fully effective, with written requests and PIPs repeating or requiring different studies. 

Increasingly, clinical studies are being conducted in new territories to achieve recruitment targets and overcome hurdles presented by the competition for patients in conventional countries such as the United States and Western Europe. There has been a significant increase in the number of all studies conducted in these nonconventional regions.

Of crucial importance in the recruitment and retention process is that of obtaining informed consent from parents (one or both) and assent from the child. This requires the provision of good information, trained staff with pediatric experience, and child friendly environments. An understanding of the motivation of parents in allowing the participation of their child in a clinical study is also helpful. 

The provision of adequate information to parents of legal guardians is important in obtaining consent and the provision of age appropriate information to the child is equally important in obtaining assent. There are ethical considerations when conducting studies in diseases where a treatment is already available, where placebo control is relevant, and in an emergency setting. All of these affect the willingness to participate in clinical research. 

Several studies have investigated the motivation of trial participants and have assessed the ability of parents to understand and memorize information given to them in the consent process. Parents asked to enroll their child in a clinical oncology or HIV study understood the aims, risks, benefits, and voluntariness of the study better than alternative treatments, procedures, and duration of participation

In a similar study, mothers of children asked to participate in a prospective asthma study reported that they were motivated by altruism and the possibility for regular check-ups in the clinic. Voluntariness was also important.

  Forty-four parents or guardians of children participating in a different asthma study reported that the most important motives for them was learning about their child's illness and helping medical knowledge.

Finally, in a tertiary care emergency setting, 136 family caregivers were asked about their perception of clinical research. Eighty-one percent agreed that physicians should do research in children, but 18% felt that physicians cared more about the research than the patients. Parents were significantly more unlikely to endorse research in an emergency setting than in a nonspecified setting.

Recruitment techniques that respond to these perceptions and expectations work best with adequate and appropriate information on clinical research in children. The disease and risk benefit of the trial together with parent and child friendly environments and adequate time for consideration are important in recruitment and retention. Also, transportation availability to investigative sites, facilities, and communication in multilingual and multiculture populations will all affect the quality and timeliness of a trial. 

In summary, pediatric research is increasing in volume and has become a global phenomenon. The special challenges of clinical studies demand careful planning and resourcing if the goals of the initiatives from regulators, governments, and health organizations are to be achieved. Integration of pediatric drug development in the planning process and assessment of the return on investment is important. 

The creation of PIPs requires an understanding of the clinical needs in children and what studies are feasible. Harmonization of regulatory requirements will hopefully lead to a reduced clinical trial burden and an avoidance of the overexposure of children to untested medicines. Clinical study risk assessment and contingency planning and the careful placement of the studies taking into account cultural, regulatory, and clinical practice differences between countries will ultimately determine the success of pediatric development. 

, MD, FFPM, FICR, is Vice President for Europe and Asia Pacific, Medical Affairs, at PharmaNet BV, Storkstraat 18-22, 3833 LB Leusden, The Netherlands, email: 

1. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on Medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (Official Journal L378,27/12/2006, 1-19).			

2. E. Tan, N.E. Cranswick, C.R. Rayner, C.B. Chapman, "Dosing Information for Pediatric Patients: Are They Really Therapeutic Orphans?" 

Feature Article

Global research in children affects industry and the trial environment.

Pediatric Trials: A Worldwide View

ACT Cover

•    In a Phase III multicenter, randomized, open-label trial comparing injectable degarelix with leuprolide, 610 prostate cancer patients were randomized to a starting dose of degarelix 240 mg for one month, followed by monthly maintenance doses of 80 mg (n=207) or 160 mg (n=202), or leuprolide 7.5 mg/month (n=201). Suppression of testosterone to castrate levels occurred significantly faster in patients receiving degarelix than in those receiving leuprolide. The study was evaluating Firmagon from Ferring Pharmaceuticals, randomized to Lupron Depot from TAP Pharmaceuticals. 

•In a large Phase III clinical trial, Tasigna® (nilotinib) 200 mg capsules demonstrated greater efficacy over Gleevec® (imatinib mesylate) tablets in the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Both drugs are marketed by Novartis. 

 identifier for this trial is NCT00802841. 

• GlaxoSmithKline announced updated long-term survival data from two Phase II studies of BEXXAR® (tositumomab and iodine I-131 tositumomab) used in either patients with previously untreated cancer of the immune system (follicular lymphoma) or in patients with cancer of the lymphocytes (non-Hodgkin's lymphoma, NHL) that no longer responded to rituximab. The first study demonstrated that, among 76 patients with previously untreated follicular lymphoma, the 10-year overall survival rate was 83% and the 10-year progression-free survival rate was 38%. The second study of NHL patients experienced an overall median survival of 6.7 years. 

• Ohr Pharmaceutical Inc. announced interim data from its Phase II clinical trial of OHR/AVR118 demonstrating the drug safely and effectively restores strength and vitality to patients suffering with cachexia, a severe wasting disorder that affects late stage cancer patients. The company anticipates it will complete the Phase II clinical trial and report the data by fall 2010. It will then request FDA approval to commence a definitive Phase III randomized, blinded clinical trial. 

• Onyx Pharmaceuticals' interim results from a Phase Ib/II 006 study, demonstrated that carfilzomib, when administered with the standard therapies lenalidomide (Revlimid®, marketed by Celgene) and low dose dexamethasone, is active and well-tolerated in patients with relapsed and/or refractory multiple myeloma. The 

 identifier for this trial is NCT00603447. A large, randomized international Phase III clinical trial studying the combination of lenalidomide and low dose dexamethasone with or without carfilzomib is planned for 2010. 

• Ambit Biosciences Corporation announced preliminary results from its open-label, dose-escalation study of its lead product candidate, AC220, in acute myeloid leukemia (AML). AC220 is a novel, orally available, small molecule that was expressly optimized as an FMS-like tyrosine kinase-3 (FLT3) inhibitor for the treatment of AML. The overall study population had a median survival time of 14 weeks. In 2010, Ambit plans to commence several clinical studies with AC220, including a registration study in AML. The 

 identifier for this trial is NCT00989261			

• Keryx Pharmaceuticals that it has been granted a Special Protocol Assessment (SPA) from the FDA for the Phase III study of perifosine in multiple myeloma. Additionally, the FDA has granted perifosine Orphan Drug and Fast Track designations in this indication. The company planned to begin the Phase III trial by end of 2009. The Division of Hematologic Neoplasia, Dana-Farber Cancer Institute was stated to be launching the trial.  

• GSK Oncology, the Oncology R&D Unit of GSK, and US Oncology have entered into a research alliance agreement. The agreement calls for US Oncology scientists and oncologists to provide patient-oriented insight to the clinical researchers at GSK. US Oncology professionals will also be critiquing and participating in the design of future clinical trials.  

• The chemotherapy drug Folotyn, approved by the FDA in September 2009 for a rare cancer, is receiving attention for its high price, the 

 reported in early December. The price is approximately $30,000 a month. Folotyn, manufactured by Allos Therapeutics, is the first approved drug for peripheral T-cell lymphoma, an aggressive blood cancer diagnosed in 5,600 U.S. patients a year. Because Folotyn works by shrinking tumors, the company maintains patients would receive the drug for a short time, making the total cost of Folotyn less than other drugs with lower monthly prices. These drugs would include, for example, Erbitux for colon cancer at $10,000 a month and Avastin at $8,800/month for lung cancer. 

• The Lung Cancer Clinical Trial Call to Action campaign was launched in November by a group of patient advocacy organizations to match lung cancer patients with currently recruiting clinical trials. The campaign is supported by Boehringer Ingelheim, Amgen, AstraZeneca, Genentech BioOncology, and Pfizer Oncology. The participating advocacy groups are Lung Cancer Alliance, CancerCare's 

, Uniting Against Lung Cancer, National Lung Cancer Partnership, LUNGevity and the Respiratory Health Association of Chicago. The service provider for the matching capability is EmergingMed. 

• The Baylor Charles A. Sammons Cancer Cancer Center has become a full member of the Southwest Oncology Group or SWOG. Baylor joined SWOG to provide important clinical trials to its patients, as well to improve the level of its research. 

• CEL-SCI has retained the services of an unnamed international CRO that specializes in late stage oncology trials to run its upcoming Phase III clinical trial in advanced primary head and neck cancers with its lead product candidate Multikane.® The trial will enroll up to 800 patients worldwide to assess overall survival when used in conjunction with standard of care treatment. 

A look at the most recent trial results in the therapeutic area of oncology.

Oncology Drug Activity

Seasonal variation in the incidence of diseases has been observed for centuries, dating back at least to ancient Greece, and yet scientific understanding of its underlying mechanisms remains relatively rudimentary for many diseases.

  Seasonality is not only an important factor in common infectious diseases—such as influenza, chickenpox, and measles—but also in noninfectious diseases such as seasonal affective disorder (SAD) and rheumatoid arthritis (RA).   

Place that next to clinical development, which at the best of times is a complex, long, frustrating process in an ever-changing regulatory environment, and you have an unenviable task for clinical trial managers. Clinical trial managers must make considerable logistical decisions and need significant depth of knowledge, including but certainly not limited to: planning timelines and projecting and managing budgets whilst at the same time ensuring the delivery of a high-quality product. However, management for seasonal diseases adds to this complexity in regard to fluctuations in the incidence of the disease studied; the recruitment of patients to coincide with a particular part of the year (dependent on latitude, of course); and the attentiveness to unexpected changes in the pattern of the disease and their implication on the running of the clinical trial.  

Mathematical modelling has provided the advancement necessary to take the hypotheses of seasonality and apply them to the field. Nevertheless, given the complexity of seasonality, a serious limiting factor to quantitative analyses and predictive models of disease patterns is the lack of long-term disease records with similar data collected over a network of spatial locations.

There are a multitude of complexities associated with running a clinical trial where a seasonal disease is the target, or could impact the trial itself. But there are strategies that can allow for the control and quality seen in less complex trial management to be transferred to the ever variable field of seasonal diseases [see sidebar]. 

The planning and management of timelines are key to successfully running a seasonal clinical trial. This includes from drafting the study design through document submissions and patient recruitment, to the trial itself. Teams employed must be focused, efficient, and resourceful, as well as fully trained in the indication studied and its seasonality. 

This section focuses largely on the discussion of infectious diseases. Ultimately, noninfectious diseases such as seasonal allergies are much more predictable, and the principles discussed here can be easily applied. However, the challenges arise when dealing with infectious diseases where seasonality can be much more volatile and where trial management must be both robust and flexible. 

Regional profiles also need to be applied when managing the global trial. Standard geography subdivides the earth into regions by latitude and there are seasonal disease fluctuations between these regions. Data for seasonal influenza, for example, can be accessed from the World Health Organization's (WHO) FluNet site, which collates global influenza data for the purpose of disease information and forecasting.  

It is common knowledge that almost 50% of delays in trials are a result of problems with subject recruitment.

  Naturally, subject recruitment for a seasonal clinical trial needs to be completed before the studied indication reaches its peak incidence (e.g., for indications with short seasons), and perhaps even before the increase in incidence begins if the study is to be carried out over the duration of the season. 

This alone raises issues. If one is recruiting patients for a seasonal indication, before that indication is evident, how can a site determine whether a patient will meet the inclusion criteria? For some indications, such as seasonal allergic rhinitis, inclusion could be based upon the patient's medical records, but for an indication such as influenza there is no way of knowing who will contract the virus. In these cases, there needs to be a rapid recruitment program in place, to enroll patients as soon as the disease is diagnosed. It would then be wise to select sites with the capabilities to recruit larger numbers of patients within short time frames. 

Conducting detailed feasibility for such diseases requires a thorough review of the incidence of the disease in previous seasons and an assessment of the factors that influenced its incidence (e.g., particularly low winter temperatures). It is also of utmost importance to submit the trial to additional countries, as a delay of one month in obtaining regulatory approval in a single country could potentially set the trial back by six months. The luxury of extending the patient recruitment period for this type of trial is simply not available. 

Study design planning, protocol writing, site selection, and investigator training need thorough attention regarding indication awareness, project management, and time management. In particular, the following should be noted: 				

			It is paramount to know the peak incidence and peak timing of the indication in different countries/regions, as this may vary considerably within a continent/hemisphere. 

The choice of participating countries/regions should be carefully selected so that regions with different timings of peak incidences and with a high probability of meeting the expected timelines can be included. 

The start-up should be carried out in phases, that is, not all regions at the same time. The aim would be to activate and give priority to those regions that have the seasonal peak sooner and direct all resources toward that region/country, followed by those regions with a later peak. This must involve careful project management because the regions will be in different phases: start-up, recruiting, and recruitment almost exhausted. 

Contingency plans should be put in place, taking into account that if at the beginning of the study the estimated predictions are not met, contingency plans are available that offer other regions for recruitment and options of different seasonal peaks—occurring later or lasting longer. The opposite situation may also occur, though less often: If recruitment expectations at the first sites initiated are exceeded and global recruitment is therefore able to end sooner than expected, additional resources/budget may have been wasted on open countries/sites with different seasonal peaks that will not ultimately be opened.      

With subject recruitment timing being such a key factor, it will be essential to submit clinical trial documents to the Ethics Committee (EC)/Competent Authority (CA) in good time in order to receive approval of a trial before the planned start of subject recruitment. Certainly in the northern hemisphere, EC/CA members, investigators, and patients tend to be on vacation during the summer months, and clinical trial approvals (as well as investigator contract approvals and patient recruitment) are therefore delayed over this time. Submissions must be timed in coordination with the EC/CAs, even if it means early submission in order to guarantee trial set-up timelines are met. 

Mathematical models and surveillance programs

Mathematical models of infectious diseases have contributed significantly to scientific understanding of the dynamics of epidemics as they spread through large populations.

The traditional model used is the SIR (susceptible-infected-resistant) model.

  This model comprises Susceptible individuals (S), Infected individuals (I), and Removed individuals (R). Each individual begins in the susceptible class, only to move to the infected class after coming into contact with an infected person. Infected individuals eventually recover from the disease and move on to the recovered class. Being "recovered" and unable to be infected once again, they are essentially removed from the population and play no further role in the dynamics. Epidemics are continuously fueled by the constant supply of new susceptibles that arise due to the birth of new individuals.

Essentially the SIR model is basic and does not account for the many factors that influence seasonal diseases. More recently, these factors have been incorporated, including seasonality and "skipping dynamics," the principles of which yield promising forecasting tools,

  which have the potential to be used for managing seasonal trials. Mathematical models have downfalls, as nature is never predictable, even if incorporating so-called chaos factors. For one particular season, the model may be way off mark, and trial start-up and progress based on such a model would be thrown out of sync with the disease incidence. 

Throughout the world there are a multitude of communicable disease surveillance programs coordinated by bodies such as the WHO, the Health Protection Agency, and the Centers for Disease Control and Prevention. Communicable disease surveillance is the continuous monitoring of the frequency and distribution of disease and death due to infections that can be transmitted from human to human or from animals, food, water or the environment to humans, and the monitoring of risk factors for those infections. 

Significantly, an important part of communicable disease surveillance is to detect the occurrence of outbreaks or epidemics so that immediate action can be taken to identify and control the source (e.g., outbreaks of food poisoning) or so that the health service is prepared to deal with increased numbers of patients (e.g., in a flu epidemic).

When managing a seasonal study, it is important to maintain good communication with the local, national, and international surveillance networks, to time study start up appropriately. 

Mathematical modelling and disease surveillance are intricately linked in the monitoring and control of communicable diseases, and it would be a serious omission on the clinical trial manager's behalf if these vast resources were not utilized in the planning and conduct of a seasonal trial. 

Conducting seasonal clinical trials is certainly complex, involving intricate time management and disease forecasting requirements. Full planning is paramount, and it has been seen that flexible patient recruitment, site selection, and document submission plans are necessary for a successful seasonal clinical trial.  

Yamin Khan*, PhD, is executive vice president, Clinical

Development for Pharm-Olam International, email: 

. Sarah Tilly is a medical writer for Pharm-Olam International, The Brackens, London Road, Ascot UK SL5 8BJ.

*To whom all correspondence should be addressed.

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Proceedings of The National Academy of Sciences

2. M. Pascual and A. Dobson, "Seasonal Patterns of Infectious Diseases," 

3. FluNet, the World Health Organisation Communicable Disease Global Atlas, 

http://gamapserver.who.int/GlobalAtlas/DataQuery/viewData.asp

4. D.P. Skoner, "Allergic Rhinitis: Definition, Epidemiology, Pathophysiology, Detection, and Diagnosis," 

Journal of Allergy and Clinical Immunology

6. L.N. Rosen, S.D. Targum, M. Terman et al., "Prevalence of Seasonal Affective Disorder at Four Latitudes," 

7. S.A. Morrissey, P.T. Raggatt, B. James et al., "Seasonal Affective Disorder: Some Epidemiological Findings from a Tropical Climate," 

Australia and New Zealand Journal of Psychiatry

8. N. Iikuni, A. Nakajima, E. Inoue et al., "What's in Season for Rheumatoid Arthritis Patients? Seasonal Fluctuations in Disease Activity," 

9. H. Aikman, "The Association Between Arthritis and the Weather," 

10. A. Fleming, J.M. Crown, M. Corbett, "Early Rheumatoid Disease," 

Infectious Diseases of Humans: Dynamics and Control

 (Oxford University Press, New York, 1991). 

12. L. Stone, R. Olinky, A. Huppert, "Seasonal Dynamics of Recurrent Epidemics," 

13. Health Protection Agency, "Surveillance," 

http://www.hpa.org.uk/webw/HPAweb&Page&HPAwebAutoListName/Page/1158313434400?p=1158313434400

Plan ahead for many seasonal diseases that could derail even the best laid clinical trials.

Flu, Season, Diseases Affect Trials

Cardiac safety is cited as the most frequent reason for drug withdrawals from the market, labeling changes, delay or refusal of regulatory approval. This places great importance on the accurate collection, analysis, and interpretation of ECG data during clinical trials.   

The FDA implemented the ICH E14 guidance document to provide recommendations to sponsors on the design, conduct, analysis, and interpretation of clinical studies that assess the cardiac effects of new drugs. The guidelines recommend that a Thorough ECG Trial (TET) should be utilized and if any cardiac concerns are raised, Phase III trials will then require more robust or intense ECG collection. 

Traditional ECG data gathering methods use a decentralized model. A decentralized system is typically carried out across multiple investigator sites using local ECG machines with paper print-out assessments. Using different model machines at different sites means that data is often inconsistent as not all machines use the same methods for calculating the resultant data. Also, different site investigators' interpretation of the results and transcription errors can create further inconsistencies in ECG results. 

A centralized approach uses digital ECGs and a core laboratory, handling the work carried out by sponsors, CROs, and individual monitoring sites. The core lab typically provides all ECG equipment to sites ensuring complete consistency throughout the trial, a faster reading process, and elimination of transcription and misinterpretation errors. Each ECG is evaluated by a qualified cardiologist to ensure data quality and integrity. 

Key costs associated with centralized ECG trials are the rental, storage, and shipping of ECG machines to investigator sites. A typical ECG machine can weigh between seven to 10 lbs and be of substantial size, with average rental costs varying between $100 and $150 per month. Reducing the acquisition fee, which includes the rental of ECG instrumentation, is one way of reducing costs. Using centralized equipment is an integral feature of a core laboratory and, therefore, the sponsor should not pay extra for machine rentals. 

The majority of ECGs performed in trials worldwide are still using a decentralized system. A common misconception is that centralized systems carry substantially more cost than the traditional decentralized approach. However, the increased usability, reliability, accuracy, and reduced investigator burden of a centralized ECG system are often overlooked. 

As demand for improved accuracy and reliability increases, new highly compact instrumentation is being explored that will substantially reduce transport and storage costs yet provide full ECG functionality in a hand-held unit. 

Integration of ECG instrumentation into existing computer systems allows key data to be automatically downloaded before a trial, saving staff time and costs associated with set-up and with programming correct algorithms and patient demographics before readings are taken. 

It remains a challenge for core labs to fully demonstrate to sponsors the added value brought about by centralization as well as the cost-savings realized through the complete study management process. 

However, innovative new instrumentation will help clinical trial sponsors ensure future patient safety and regulatory compliance by reducing site burden, increasing accuracy, reliability, usability, and accessibility to quality results. 

Executive Vice President Cardiac Safety Operations, ERT 

A Closing Thought

Improvements in data quality and data capture and reduced workload for sponsors and sites are evident.

Cardiac Safety: Cost to Trials

The New Year has seen the introduction of a fresh regime at the European Medicines Agency (EMEA). Amendments to the agency's organizational network, fee structure, and Web presence take effect this month. 

Among the highlights of the new system is the integration of human pre- and postauthorization activities into one unit. The move is designed to guarantee seamless lifecycle management of medicines. In addition, the creation of a unit for patient health protection aims to strengthen the EMEA's focus on drug safety monitoring, and a dedicated group for the management of product data and documentation should help to improve the efficiency of data management processes (a chart is available at 

http://www.ema.europa.eu/pdfs/general/direct/organisation.pdf

The EU's regulatory agency aims for efficiency with recent changes.

Applied Clinical Trials-01-01-2010

Applied Clinical Trials Digital Edition - January 2010

Business and People Update January 2010

Trials in Oncology only Going Up

Pediatric Trials: A Worldwide View

ACT Cover

Oncology Drug Activity

Flu, Season, Diseases Affect Trials

Cardiac Safety: Cost to Trials

EMEA Implements Wave of Changes

Agency Reorganizes for European Future

Research Faces Challenges in 2010

With Clinical Data, Less is More