Seasonality: The Clinical Trial Managers Logistical Challenge

Written by Yamin Khan, PhD and Sarah Tilly

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 under lying mechanisms remains relatively rudimentary for many diseases.1 Seasonality is not only an important factor in common infectious diseases (such as influen za, chickenpox and measles) but also in noninfectious diseases such as seasonal affective disorder (SAD) and rheumatoid arthritis (RA). The complexity of sea sonality of both infectious and noninfectious diseases incorporating as it does the diverse disciplines of epidemiology, pathology, immunology, meteorology, population dynamics and statistics has resulted in few coherent hypotheses that satisfactorily combine each contributing factor.2 There are plenty of plausible qualitative theories surrounding disease seasonality, but, with a few exceptions, supportive quantitative evidence is somewhat lacking. Clinical development is, at the best of times, a com plex, long, frustrating process in an ever changing regulatory environment. It is akin to working hard for up to 10years to answer one question, only to realise that in the meantime the question itself has changed. In the sometimes futile attempt to ensure the timely delivery of patient data to the regulators, the manage ment of clinical research involves a great degree of planning, organising and execution by highly qualified and professional personnel, as well as involving some elements of chance. The clinical trial managers who are bestowed with this unenviable task are faced with considerable logistical decisions and the need for sig nificant depth of knowledge, including but certainly not limited to: planning timelines, projecting budgets and managing budgets, whilst at the same time ensur ing the delivery of a high quality product. However, management for seasonal diseases adds to this com plexity, regarding fluctuations in the incidence of the disease studied; the recruitment of patients to coincide with a particular part of the year (dependent on lati tude, of course) and the attentiveness to unexpected changes in the pattern of the disease and their implica tion on the running of the clinical trial.

1. Introduction

Mathematical modelling has provided the advance ment 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 loca tions.3 It is therefore the aim of this paper to discuss the multitude of complexities associated with running a clinical trial for a seasonal disease, and to suggest potential strategies as well as further research neces sary to improve the execution of such trials, in order for the control and quality seen in less complex trial management to be transferred to the ever variable field of seasonal diseases. Firstly, a range of both in fectious and noninfectious diseases whose incidences are affected by changes in seasonality (some more predictable than others) are discussed. There is then a discussion of regional fluctuation in influenza inci dence, as an example of a seasonal disease. Finally, this knowledge is applied to the management of sea sonal clinical trials.

2. Seasonal Disease Profiles

In this section five seasonal diseases are discussed (influenza, seasonal allergic rhinitis [SAR], seasonal affective disorder [SAD], rheumatoid arthritis [RA] and malaria). Each of these indications are seasonal in different ways. These brief overviews by no means present an exhaustive resource, but simply aim to highlight the varied driving forces behind seasonality of infectious and noninfectious diseases. Please see Table1 for a more extensive list of seasonal diseases. 2.1 Influenza Influenza (flu), an acute viral respiratory disease, is probably the seasonal disease that immediately comes to mind, and is perhaps of the most profound in terest, as it is responsible

for much of the seasonal variation in other infectious and noninfectious causes of morbidity and mortality.1 In 2008 alone there were 70611 cases of seasonal in fluenza (influenza A and B) worldwide, with the highest incidence being in the United States (41,106 cases).4 In temperate regions, incidence of infections are characterised by flu seasons, generally exhibiting a marked increase during the winter months, with tropi cal regions showing a much less defined pattern. Factors contributing to the seasonality of influenza can be divided into four categories:

known as winter SAD). Rates of winter SAD have been found to be significantly higher at the more northern latitudes.7 As for allergic rhinitis, the direct link between SAD incidence and seasons is also evi dent: as the days grow shorter, daylight hours decrease. In fact, treatment for SAD often involves using artifi cial light as a supplement for the reduced daylight hours. In tropical regions winter SAD is very rare, if not non-existent although there are potential cases of summer SAD (depression as a result of extreme sum mer conditions) reported.8 Rheumatoid arthritis, a chronic autoimmune disease that is charac terised by pain, stiffness, inflammation, swelling and sometimes destruction of joints, is more often known by its sufferers as a seasonal dis ease than the general public. The weather and seasonal changes are often suggested by patients as causes for changes in joint related symptoms.9 Results from sci entific studies however, show discrepancies, with some indicating that the winter months cause more se vere symptoms9,10,11 and some indicating that the spring months cause more severe symptoms.9 Others reported that the increase in absolute humidity in sum mer is unfavourable to symptoms and disease activity, but that due to less clothing and air conditioning, there is lower vapour pressure on the skin, allowing for a better outcome for RA symptoms.12 There are also in dications that less exposure to light during the winter months (causing proinflammatory cytokine and Vita min D changes) may be the cause of RA symptom exacerbation.9 However, there is a general consensus that RA symptoms worsen during the wet and/or cold months. 2.5 Malaria Malaria is an acute or chronic disease caused by the presence of spo rozoan parasites of the genus Plasmodium in the red blood cells, transmitted from an in 2.4 Rheumatoid Arthritis

Pathogen survival: ambient temperature, relative humidity, vapour pressure Pathogen evolution: antigenic drift (rapid muta tion), antigenic shift (re-assortment of genome) Host resistance to infection: melatonin and vita min D levels (fluctuate with light/dark cycles) Host behaviour: amount of time spent indoors, ag gregation of people

Allergic rhinitis (AR) is a heterogeneous disor der that despite its high prevalence is often un diagnosed. It is characterised by one or more symptoms includ ing sneezing, itching, nasal congestion and rhinorrhea. Many causative agents have been linked to AR includ ing pollens, molds, dust mites and animal dander. Seasonal allergic rhinitis (SAR) is fairly easy to iden tify because of the rapid and reproducible onset and offset of symptoms in association with pollen expo sure5, as well as other allergens such as ragweed and fungus. In SAR, with relevant allergen sensitisation, the link between the seasonal allergen exposure and rhinitis is clear cut.6 2.3 Seasonal Affective Disorder Seasonal affective dis order is a form of depression that tends to occur as the days grow shorter during the au tumn and winter (this is

2.2 Allergic Rhinitis

fected to an uninfected individual by the bite of Anophelese mosquitoes, and characterised by periodic attacks of chills and fever that coincide with mass de struction of blood cells and the release of toxic substances by the parasite at the end of each reproduc tive cycle. With malaria, it is not necessarily the symptoms of disease that are seasonal, but the timing and the length of the transmission period. In this case, it is the action taken to prevent the transmission of the disease by the vector that is seasonal, and must coin cide with the transmission period. Correlations of fluctuations in malaria rates with rainfall and river level in relation to the periodic availability of breeding habitats for the malaria vector have been observed. Peaks in biting densities correlated well with periods of (i) high water level in the long rainy season, (ii) low water level in the long dry season, and (iii) abundant rainfall in the short rainy season.13 Minimum tempera ture, irrigation and sea surface temperatures (such as the El Nio Southern Oscillation) also show signifi cant correlations with malaria incidence.14,15

3. regional Profiles

Standard geography subdivides the earth into regions by latitude: the northern temperate regions (north of the Tropic of Cancer), the southern temperate regions (south of the Tropic of Capricorn) and the tropical re gions (between the Tropic of Capricorn and the Tropic of Cancer). The reason for looking at this division in this article is that the majority of seasonal diseases are affected by climate and temperature, which are largely an effect of a countrys position in relation to the sun as a result of the tilt of the earths axis. Besides the effects of solar radiation and its variations, climate is also influenced by secondary influences, including position relative to land and water masses, altitude, topography, prevailing winds, ocean currents, and prevalence of cyclonic storms.16 A map of the world indicating these differences in cli mate in Illustration 117, presented below. One example of the difference in seasonal disease fluctuations between these regions is displayed in

World Map of Kppen-Geiger Climate Classification

Tropic of Cancer

Tropic of Capricorn

Tropical rainforest monsoon savannah

Arid desert hot desert cold steppe hot steppe cold dry-hot s dry-warm s

Temperate dry-w/hot s dry-w/hot s dry-w/cold s hot summer warm s cold s dry/hot s dry/warm s dry/cold s dry s/cold w

Cold dry w/hot s dry w/hot s dry w/cold s dry w/cold w hot summer warm s cold s cold w

Polar tundra frost

0 1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 Week

Total lncidence of Influenza A & B Detection

the figures below. Data for seasonal influenza (A and B) detection was taken from the World Health Or ganisation (WHO) FluNet site, which collates global influenza data for the purpose of disease information and forecasting.

Figure 2

Figure 2
800

Total Incidence of Influenza A and B by Latitude in 2007

N Hemisphere S Hemisphere Tropics

700

600

Total incidence of Influenza B Detection Total incidence of Influenza A &A B& Detection

Figures 1 and 2 show the total incidence of influenza in 2008 and 2007, respectively. In 2008, the seasonali ty of the disease in the northern hemisphere is evident, with peak incidence during the winter months, low in cidence during the spring and summer months, and a rise in incidence again at the beginning of winter. To Figure 3 a certain extent, the 2007 figures show a similar pat Figure 3 tern, but it must be noted that the total number of data Figure 3 points for 2008 were 2283, and for 2007 were only 390 (earlier years have even fewer data points). This highlights further the lack of robust, easily-accessible historical data for seasonal diseases.
400 300 200 100 0 1 4
250 250 200 200 150 150

500

10

13

16

19

22

25

28

31

34

37

40

43

46

49

52

Week

Total Incidence of Influenza A & B in the Southern Hemisphere in 2008 Total Incidence of Influenza A & B in the Southern Hemisphere in 2008

Total Incidence of Influenza B Detection Total Incidence of Influenza A &A B& Detection

Looking at the 2008 data, the fluctuations in the south ern hemisphere and tropics are less evident, perhaps partly due to the lower population in the southern hemisphere18 and partly due to the fact that fewer data were available for these regions. However, when dis played individually (Figures 3 and 4) it is evident that Figure 4 Figure 4 the fluctuations in the southern hemisphere are a mir Figure 4 ror image of those in the northern hemisphere, with peaks and troughs corresponding to the same seasons. Little fluctuation in incidence is seen in the tropics, where seasons are much less pronounced, if not totally absent.
100 100 50 50 0 0 1 1 4 4

7 7

10 10

13 13

16 16

19 19

22 22

25

28 Week

31 31

34 34

37 37

40 40

43 43

46 46

49 49

52 52

25 Week 28

Total Incidence of Influenza A & B in the Tropics in 2008 Total Incidence of Influenza A & B in the Tropics in 2008

250

250

200

200

150

150

Figure 1

Figure 1
Total Incidence of Influenza A and B by Latitude in 2008
7000 N Hemisphere S Hemisphere Tropics

100 100

50 50

0 0 1 1 4 4 7 7 10 10 13 13 16 16 19 19 22 22 25 28 Week 31 31 34 34 37 37 40 40 43 43 46 46 49 49 52 52 25 Week 28

6000 Total Incidence of Influenza A & B Detection

5000

4000

3000

2000

1000

0 1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 Week

Figure 2
Total Incidence of Influenza A and B by Latitude in 2007
800 N Hemisphere S Hemisphere Tropics

4. INCORPORATING SEASONALITY IN CLINICAL TRIAL MANAGEMENT 4. INCORPORATING SEASONALITY IN CLINICAL TRIAL MANAGEMENT 4.  Incorporating Seasonality in Clinical 4.1 Study Plan and Timeline Flexibility 4.1 Study Plan and Timeline Flexibility Trial Management It is evident from the data and information presented that the planning and management It is evident from the data and information presented that the planning and trial. management of timelines are going to be key to successfully running a seasonal clinical From of timelines are going to be key todocument successfully running a and seasonal clinical trial. From 4.1 Study Plan and Timeline Flexibility drafting the study design, through submissions patient recruitment, to the drafting theof study design, through document submissions and patient and recruitment, to the conducting the trial itself, greatthe care must be taken in the planning meeting of It is evident from data and information presented conducting of theemployed trial itself, great care must be taken inand the resourceful, planning and meeting timelines. Teams must be focussed, efficient, as well as of fully timelines. Teams employed must be focussed, efficient, and resourceful, as well that the planning and management of timelines areas fully trained in the indication studied and its seasonality. trained in the indication studied and its seasonality. going to largely be key todiscussion successfully running a Ultimately, seasonal This section focuses on the of infectious diseases. This section focuses largely on the discussion of infectious diseases. Ultimately, noninfectious diseases, such as seasonal allergies, are much more predictable, and the clinical trial. From drafting the are study design, through noninfectious diseases, such as seasonal allergies, much more predictable, and the

700 of Influenza A & B Detection

600

document submissions and patient recruitment, to the conducting of the trial itself, great care must be taken in the planning and meeting of timelines. Teams em ployed must be focussed, efficient, and resourceful, as

6 6

500

400

well as fully trained in the indication studied and its seasonality. This section focuses largely on the discussion of in fectious diseases. Ultimately, noninfectious diseases, such as seasonal allergies, are much more predicta ble, and the principles discussed below can be easily applied. However, the challenges really arise when dealing with infectious diseases, where seasonality can be much more volatile, and where clinical trial management must be at the same time both robust and flexible. 4.1.1  Patient Recruitment, Study Planning and Timelines It is common knowledge that almost 50% of delays in clinical trials are a result of problems with patient recruitment.19 Naturally, patient recruitment for a sea sonal clinical trial needs to be completed before the studied indication reaches its peak incidence, and perhaps even before the increase in incidence begins (e.g. for indications with short seasons), 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 SAR, inclusion could perhaps be based upon the patients medical records, but for an indication such as influenza, there is no way of knowing who will contract the virus. In these cases, there perhaps needs to be a rapid recruitment programme in place, to enrol patients as soon as the disease is diagnosed. It would also be wise to select sites with the capabili ties to recruit larger numbers of patients within short timeframes. 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. par ticularly 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 ap proval in a single country could potentially set the trial back by six months. The luxury of extending the pa tient recruitment period for this type of trial is simply not available. Study design planning, protocol writing, site selection and investigator training to name a few 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 coun tries/regions as this may vary considerably within a continent and/or 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 (i.e. not all regions at the same time). The aim would be to activate and give priority to those regions which have the seasonal peak sooner and direct all resources towards that region/country, followed by those regions with a later peak. This must involve careful project management because the regions to be coordinated will be in different phases: some of them in start-up, some recruiting, and some with 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 re cruitment and options of different seasonal peaks occurring later or lasting longer. The opposite situation may also occur, though less often: if re cruitment 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 ul timately be opened.

4.1.2 Document Submissions With patient recruitment timing being such a key factor, it will be essential to submit clinical trial doc uments to the Ethics Committee (EC)/Competent Authority (CA) in good time, in order to receive ap proval of a trial before the planned start of patient 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 setup timelines are met. 4.2 Mathematical Modelling of Seasonal Diseases Mathematical models of infectious diseases have con tributed significantly to scientific understanding of the dynamics of epidemics as they spread through large populations.20 The traditional model used is the SIR (susceptibleinfected-resistant) model.21 This model comprises Susceptible individuals (S), Infected individuals (I), and Removed individuals (R). Each individual begins in the susceptible class S, only to move to the infected class I after coming into contact with an infected per son. Infected individuals eventually recover from the disease and then move on to the recovered class R. Be ing 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 fuelled by the constant supply of new susceptibles that arise due to the birth of new indi viduals.20 Essentially the SIR model is relatively basic, and does not necessarily account for the numerous factors dis cussed in Section 2. More recently, these additional factors have been incorporated, including seasonal ity and skipping dynamics, the principles of which yield promising forecasting tools20,22, that have the po tential to be used for managing seasonal trials. Naturally, any mathematical model has its downfalls, as nature is never entirely predictable, even if incor porating so-called chaos factors. Ultimately, 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 inci dence. 4.3  Communicable disease surveillance programmes Throughout the world there are in place a multitude of communicable disease surveillance programmes, coordinated by bodies such as the WHO, the Health Protection Agency (HPA) and the Centers for Disease Control and Prevention (CDC). Communicable dis ease surveillance is the continuous monitoring of the

frequency and the distribution of disease, and death, due to infections that can be transmitted from human to human or from animals, food, water or the environ ment to humans, and the monitoring of risk factors for those infections. Significantly, an important part of communicable disease surveillance is also to detect the occurrence of outbreaks or epidemics so that im mediate 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). 23 It is of great importance, therefore, that when man aging a seasonal study, good communication is maintained with the local, national and international surveillance networks, preventing study start up being initiated at any time other than within the ideal win dow of disease incidence. 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 managers behalf if these vast resources were not utilised in the planning and conduct of a seasonal clinical trial. 4.4 Resourcing Having discussed the planning, monitoring and flex ible time management needed to support a seasonal clinical trial, it is of no surprise that the teams in volved need to be fully resourced, they need to be efficient and they need to have access to a whole host of information, including disease surveillance net works. Resourcing is one of the greatest challenges in the execution of these trials: it is not unfeasible to complete these trials much earlier than planned, much later than planned, or in a different region to that origi nally planned all need thorough and comprehensive resource planning. Choosing such teams, including suitable vendors of the highest quality, is no easy task, and must not be taken lightly. However, efforts invested at this early stage will undoubtedly pay off further down the line.

5.  Conclusion: feasibility, Financial Costs and Rewards

Conducting seasonal clinical trials is certainly com plex, 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 nec essary for success. Having discussed the intricacies of seasonal clinical trial management, the question that will arise in any discerning managers mind is whether such complex studies are financially viable; whether the initial investment pays off in terms of overall profit. Certainly, there are significant opportunities (both in terms of public health and financial gain) in conduct ing seasonal clinical trials, and there is undoubtedly a gap in the market for such studies. However, detailed research must be carried out in order to forecast the necessary expenditure, potential profit and ultimate feasibility of conducting such trials. Nevertheless, with the long term in mind, quality work for the most part does pay off. Having conduct ed a successful seasonal clinical trial the profile of the managing organisation will surely be greatly im proved; respect among the industry will be enhanced; and subsequently overall profitability should in the fullness of time see a marked increase.

Weather, International Journal of Biometeorology, 40 (4) 192 199 (1997). 11 A. Fleming, J.M. Crown, M. Corbett, Early Rheumatoid Disease, Annals of Rheumatic Disease, 35 357360 (1976). 12 W.R. Patberg, J.J. Rasker, Weather Effects in Rheumatoid Arthritis: from Controversy to Consensus. A Review, Journal of Rheumatology, 31 (7) 13271334 (July 2004). 13 J.A. Rozendaal, Relations Between Anopheles darlingi Breeding Habitats, Rainfall, River Level and Malaria Transmission Rates in the Rain Forest of Suriname, Medical and Veterinary Entomology, 6 (1)16-22 (January 1992). 14 M.C. Thomson, S.J. Mason, T. Phindela, et al, Use of Rainfall and Sea Surface Temperature Monitoring For Malaria Early Warning in Botswana, American Journal of Tropical Medicine and Hygeine, 73 (1) 214221 (2005). 15 M.L.H. Mabaso, M. Craig, A. Ross, et al, Environmental Predictors of the Seasonality of Malaria Transmission in Africa: The Challenge, American Journal of Tropical Medicine and Hygeine, 76 (1) 3338 (2007) 16 The Columbia Encyclopedia, Climate, Sixth Edition, 2008. Encyclopedia.com. http://www.encyclopedia.com (accessed 01June, 2009). 17 Kppen-Geiger climate map, World Climate Map, http:// www.civenv.unimelb.edu.au/~mpeel/koppen.html (Adapted from Peel et al (2007)). 18 Population 1995, Center for Sustainability and the Global Environment, Atlas of the Biosphere, http://www.sage.wisc.edu/ atlas/maps.php?datasetid=1&includerelatedlinks=1 &dataset=1 (accessed 01 June, 2009). 19 A. Sahoo, Patient Recruitment and Retention in Clinical Trials - Emerging strategies in Europe the US and Asia, Business Insights, June 2007. 20 R. Olinky, A. Huppert and L. Stone, Seasonal Dynamics and Thresholds Governing Recurrent Epidemics, Journal of Mathematical Biology, 56 (6) 827839 (2008). 21 R.M. Anderson and R.M. May, Infectious Diseases of Humans: Dynamics and Control (Oxford University Press, New York, 1991). 22 L. Stone, R. Olinky and A. Huppert, Seasonal Dynamics of Recurrent Epidemics, Nature, 446 (7135) 533-536 (March 2007). 23 Surveillance, Health Protection Agency, http://www.hpa. org.uk/webw/HPAweb&Page&HPAwebAutoListName/Page/11583 13434400?p=1158313434400 (accessed 26May, 2009).

6. References
1 M. Lipsitch and C. Viboud, Influenza Seasonality: Lifting the Fog, Proceedings of The National Academy of Sciences, 106 (10) 3645-3646 (March 10, 2009). 2 E. Lofgren, N.H. Fefferman, Y.N. Naumov, et al, Influenza Seasonality: Underlying causes and Modeling Theories, Journal of Virology, 81 (11) 54295436 (June 2007). M. Pascual and A. Dobson, Seasonal Patterns of Infectious Diseases, PLoS Medicine, 2 (1) e5 (January 2005). FluNet, the World Health Organisation Communicable Disease Global Atlas http://gamapserver.who.int/GlobalAtlas/ DataQuery/viewData.asp (accessed 19 May 2009). D.P. Skoner, Allergic Rhinitis: Definition, Epidemiology, Pathophysiology, Detection, and Diagnosis, Journal of Allergy and Clinical Immunology, 108 (1) S2-S8 (July 2001). A.S. Kemp, Allergic Rhinitis, Paediatric Respiratory Reviews, 10 (2) 63-68 (June 2009). L.N. Rosen, S.D. Targum, M. Terman, et al, Prevalence of Seasonal Affective Disorder at Four Latitudes, Psychiatry Research,31 (2) 131-144 (February1990). 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, 30 (5) 579-586 (October 1996). N. Iikuni, A. Nakajima, E. Inoue, et al, Whats in Season for Rheumatoid Arthritis Patients? Seasonal Fluctuations in Disease Activity, Rheumatology, 46 (5) 846848 (January 2007). H. Aikman, The Association Between Arthritis and the

3 4

6 7

Authors: Yamin Khan, PhD, is Executive Vice Pres ident at Pharm-Olam International, email yamin. [email protected]. Sarah Tilly is a Medical Writer for Pharm-Olam International.

10

Table 1 A Collection of Seasonal Diseases Sources: POI country questionnaires and Medline Plus, http://www2.merriam-webster.com/cgi-bin/mwmednlm (accessed 01 June, 2009)
Common/clinically important seasonal indications Allergic keratoconjunctivitis Description Climate required to initiate peak Warm/humid Other factors influencing peaks Fungus spores, increase in pollen count, dust, animal hair High/increase in pollen count, pollution, pollen species involved Increase in pollen count, chemical substances, medicines Superheating, hyperhidrosis Society

Combined inflammation of the cornea and conjunctiva, caused by allergens Inflammation of the mucous membrane of the nose marked especially by rhinorrhea, nasal congestion and itching, and sneezing caused by exposure to an allergen A chronic lung disorder that is marked by recurring episodes of airway obstruction (as from bronchospasm) that is triggered by hyperreactivity to various stimuli (as allergens or rapid change in air temperature) Inflammation of the skin characterised by symptoms (as asthma, hay fever, or hives) produced upon exposure, especially by inhalation to the exciting environmental antigen An acute contagious disease of the upper respiratory tract and is caused by any of several viruses (as a rhinovirus or an adenovirus) A condition especially caused by atherosclerosis that reduces the blood flow through the coronary arteries to the heart muscle and typically results in chest pain or heart damage Chronic ileitis that typically involves the distal portion of the ileum, often spreads to the colon, and is characterized by diarrhoea, cramping, and loss of appetite and weight with local abscesses and scarring Degenerative disease of a joint Dengue (an acute infectious disease that is caused by a single-stranded RNA virus of the genus Flavivirus transmitted by mosquitoes of the genus Aedes) marked by hemorrhagic symptoms (as hemorrhagic lesions of the skin, thrombocytopenia, and reduction in the fluid part of the blood) A state of being depressed as a state of feeling sad or a psychoneurotic or psychotic disorder marked especially by sadness, inactivity, difficulty with thinking and concentration, a significant increase or decrease in appetite and time spent sleeping, feelings of dejection and hopelessness, and sometimes suicidal thoughts or an attempt to commit suicide Inflammation of the brain usually caused by a virus A metabolic disease marked by a painful inflammation of the joints, deposits of urates in and around the joints, and usually an excessive amount of uric acid in the blood Any of several acute highly contagious respiratory diseases caused by strains of three major orthomyxoviruses A disorder characterised by skin inflammation An acute inflammatory disease that is usually characterised initially by the skin lesion erythema migrans and by fatigue, fever, and chills that is caused by a spirochete of the genus Borrelia (B. burgdorferi) transmitted by the bite of a tick especially of the genus Ixodes

Allergic rhinitis

Warm spring

Asthma

Warm conditions

Atopic dermatitis Common cold (paediatrics)

Hot climate Cold weather, moisture Winter Early spring, autumn Spring and autumn Rainy weather

Coronary heart disease

Cold weather exposure

Crohns disease Degenerative arthropathy

Personal stress High humidity Sanitary conditions for storing water

Dengue hemorrhagic fever

Depression

Absence of sunshine

Winter blues

Epidemic encephalitis (tick) Gout

Warm dry weather Winter Cold weather, low temperatures / low humidity Summer

Location, vaccination Low temperature High population density, health status (risk groups) , immunity, vaccination Hot weather, sun

Influenza Lupus Erithematosus

Lyme borreliosis

Warm dry weather

Location

Common/clinically important seasonal indications

Description An acute or chronic disease caused by the presence of sporozoan parasites of the genus Plasmodium in the red blood cells, transmitted from an infected to an uninfected individual by the bite of anopheline mosquitoes, and characterised by periodic attacks of chills and fever that coincide with mass destruction of blood cells and the release of toxic substances by the parasite at the end of each reproductive cycle An acute contagious disease that is caused by a paramyxovirus of the genus Morbillivirus (species Measles virus); any of various eruptive diseases (as German measles) A disease of the lungs that is characterised especially by inflammation and consolidation of lung tissue followed by resolution, is accompanied by fever, chills, cough, and difficulty in breathing, and is caused chiefly by infection A chronic skin disease characterised by circumscribed red patches covered with white scales Infection with or disease caused by bacteria of the genus Salmonella typically marked by gastroenteritis but often complicated by septicemia, meningitis, endocarditis, and various focal lesions (as in the kidneys) Depression that tends to recur as the days grow shorter during the fall and winter Inflammation of a sinus of the skull

Climate required to initiate peak

Other factors influencing peaks

Malaria

Monsoon

Warm humid weather and stagnant water

Measles

Spring

Infection, contact with children

Pneumonia

Winter

Cold weather, pollution

Psoriasis

Summer

Hot weather, sun Lack of adequate sanitary conditions for food Reduced sunlight Increase in pollen count Concomitant infections Hot weather, sun

Salmonellosis Seasonal affective disorder

Hot climate Winter Warm spring / summer months Cold winter months Summer

Sinusitis

Thyroid gland diseases

Diseases of, relating to, affecting, or being the thyroid gland A usually chronic highly variable disease that is usually caused by a bacterium of the genus Mycobacterium (M. tuberculosis), is usually communicated by inhalation of the airborne causative agent, affects especially the lungs but may spread to other areas (as the kidney or spinal column) from local lesions or by way of the lymph or blood vessels, and is characterised by fever, cough, difficulty in breathing, inflammatory infiltrations, formation of tubercles, caseation, pleural effusion, and fibrosis A hepatitis that is common in some developing countries, usually contracted from sewage-contaminated water, and is caused by a highly variable single-stranded RNA virus (species Hepatitis E virus) of uncertain taxonomic affinities but related to members of the family Caliciviridae

Tuberculosis

Summer

Contamination of drinking water and airborne vectors

Viral Hepatitis E

Summer

Sewage as a source of contamination of drinking water

Patient Enrollment Experts Across Emerging

and

Traditional Markets

Rhinoconjunctivitis (Grass Allergy) The sponsor of an allergic rhinoconjunctivitis study selected Pharm-Olam and another CRO (global company) for this competitive enrollment study. Pharm-Olam delivered 235 or 65% out of the actual 362 randomized patients, despite the fact that the other CRO had 50% more sites and several weeks longer to recruit patients.
Country Sites Enrollment Period Total Patients Patients per Week

Seasonal Rhinitis By the end of the study Pharm-Olam was the highest recruiter with 263 randomized patients. In fact, out of 15 countries participating in the study, Pharm-Olam recruited almost 30% of all patients. The patient data collected from Pharm-Olam sites was of high quality with less than 2 queries per randomized patient. The recruitment was made respecting the set timelines at an appropriate speed. The team at Pharm-Olam, and their standards were well adapted to our working relationship. Communication between Pharm-Olam and us was good, and they are showing good reactivity to emitted requests. The work performed by Pharm-Olam was kept within the study budget and their experience with Ethics Committees/Health Board was helpful in obtaining agreements from ECs. In conclusion, Pharm-Olam International gave us entire satisfaction. Reference Letter from Sponsor Study Manager. Data from study was later used to support successful US NDA approval in pediatric indication

Pharm-Olam Poland Pharm-Olam Germany Other CRO in France, Italy, UK, Belgium, Netherlands

10 11

4 weeks 5.5 weeks

64 171

1.60 2.83

31

over 7 weeks

127

Less than 0.59

Comprehensive Services and Multi-National Coverage

 Rapid Patient Recruitment  Monitoring  Regulatory/Ethics Submissions  Data Management  Biostatistics  Project Management  Pharmacovigilance  Import/Export Licenses  Contract Negotiation and Administration  Product Registration  Feasibility Studies P  rotocol Design H  ealth Outcomes Research D  SMB Preparation Q  uality Control/Assurance M  edical Writing  CTMS  Translations  Registry Studies  Investigator Meetings & Training

 ontact Pharm-Olam C for a complimentary feasibility study

Global Headquarters 450 N. Sam Houston Pkwy E., Suite 250 Houston, TX 77060 USA +1 (713) 559-7900 www.pharm-olam.com European Headquarters The Brackens, London Road Ascot, Berkshire SL5 8BJ +44 (0) 1344 891121 [email protected]

POI Staff Regional Partners Offices