White Paper on Key Challenges in Patient Recruitment - CNS (Central Nervous System)

1. CNS
Key Challenges in Patient
Recruitment
(South East Asia can help)
WHITE PAPER

2. WHITE PAPER
CNS: Unleashing Opportunity
CNS: Unleashing Opportunity
Central nervous system (CNS) disorders account for more than 40 percent of the total disease burden (TBD) in the
world’s seven largest pharmaceutical markets. Therapies for psychiatric and neurological disorders constitute nearly 21.4
percent of the total pharmaceutical market. Despite the enormous volume of on-going clinical research in CNS therapeutic
area, the pathophsiology of most of the CNS disorders is still poorly understood.
There are significant unmet medical needs in the treatment of Alzheimer’s disease, cognitive disorders, stroke, multiple
sclerosis, Parkinson’s disease, and major psychiatric disorders; since the majority of these disorders are chronic in nature,
the demand for clinical research in CNS newer targets/investigational drugs should grow rapidly in the years ahead.
Current treatment patterns show low patient response rates of 50 – 60 %
Response Prediction in majority of the disorders needs individualized/personalized therapies.
The safety profile of most of the marketed drugs not ideal
This all require Sponsors to translate the clinical research to bed-side medicines to tap the significant market potential
without any significant challenges.
Challenges in CNS Patient recruitment
The CNS drug development is one of the fastest growing markets, and more than 35% increase is observed in the patient
pool of more than 10 million members for almost every neurological condition.The increase in patients who are seeking
clinical-trial opportunities attributed to growing disease prevalence and people taking a more proactive approach to
their healthcare needs. This increase in clinical-trial activity is due to the potential therapeutic benefits not addressed by
today’s array of approved CNS drugs. There is a more substantial need for increased intensive patient-recruitment
support across the spectrum of CNS disorders.
CNS patient recruitment lags behind in patient-recruitment efforts as compared to oncology and cardiology, for several
reasons. This is because, the patients who have CNS disorders often have impairments in their thinking process,
therefore, experience difficulty consenting to, and participating in, the clinical-trial process. Many of the diagnostic/
evaluation tools required for trial protocols are extremely lengthy for CNS conditions to ensure that the subjects fall
within the inclusion/exclusion criteria. The diagnosis assessments for most of the CNS disorders generally involve input
from the potential patient, caregiver, and a clinician to establish a baseline from which expected improvement can be
measured. Therefore, the person responsible for patient recruitment must understand that both patient and caregiver
are going to be required to complete multiple tests and visits, keep diaries, and report observations.
In general, only about 20% of patients are aware of clinical trials, and of those, only one-third will participate in any
clinical trial. Patient recruitment for the CNS patient population, therefore, presents additional barriers that must be
addressed by the entire industry. All these challenges can be addressed through patient/caregiver driven approaches and
strategies. Sponsors and sites should design and implement caregiver programs that work in conjunction with the trial
to allow the caregiver a few hours of respite while the patient is undergoing the long tests and procedures.
The three most important issues to be considered when recruiting patients with chronic CNS disorders are motivation,
location, and condition. Therefore, it is essential to prescreen the study candidates based on these requirements to help
sponsors avoid the cost of recruitment. Hence the key to conducting recruitment effectively lies in conducting an
honest, early recruitment feasibility assessment to determine the idiosyncratic challenges posed by a given study and
the development of an effective recruitment plan well in advance of first patient in. That might include appropriate
timelines and contingency plans. Since the marginal cost per patient for a trial in rescue mode is typically two to three
times greater than the cost of the same patient coming from a recruitment strategy initiated with the trial itself.
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CNS: Unleashing Opportunity
Each condition represents a unique patient population, caregiver constituency, and physician relationships, all of which
factor heavily in the outcome of a successful recruitment strategy. In addition, each trial presents its own set of
characteristics, for example, number of sites, choice of principal investigator by specialty and referral network, standard
of care vs. drug under investigation, and trial design issues, and so on, which must be factored into assessing the
feasibility of recruitment.
The patient-recruitment efforts will benefit from the general population developing a better overall understanding of
clinical trials. An effective strategy is to consider the impact that trial participation will have on the lives of patients and
caregivers beyond the realm of study visits and research sites. Participation in CNS trials will improve when the sponsors
able to identify strategies that overcome the obstacles affecting patients and families as a result of trial participation.
In the past, sponsors could count on a fairly well-defined pool of expert investigators to provide them with the patients
required for their studies. While this pool of seasoned investigators has expanded modestly over time, it has not kept up
with the industry’s pace of research in terms of access to the number of patients needed for clinical trials conducted today.
Clinical trials in Depression: Challenges and Opportunities
The design and evaluation of clinical trials with antidepressant drugs still constitutes a big challenge. According to an
analysis, most of the known effective and marketed antidepressants had failed to show a statistically significant drug
effect. Since the drug regulatory authorities currently demands two positive pivotal clinical trials before registration
is considered in most cases due to the high failure rate. Undoubtedly, one of the important factors contributing to
this high failure rate is disease-related like high variability in response, the heterogeneity of patients being diagnosed
with major depressive disorder (MDD), the difficulties in objectively measuring the severity of depression and the
high placebo effect. These disease-related causes are generally hard to address in individual trials. For example, a
possible solution to patient heterogeneity would be to refine the inclusion/exclusion criteria as to ensure more
homogeneous groups of patients. The variability in response for example has often been assigned to the placebo
effect. In fact, changes in clinical trial design have been suggested to mitigate this effect. Single- and double-blind
placebo run-in phases have been introduced to detect placebo responders early in the trial, albeit with limited
effectiveness. The difficulties in assessing depression severity and the known limitations of clinical rating scales may
be solved by developing multidimensional endpoints, or alternatively, by allowing for the introduction of composite
measures in which additional objective (bio) markers of disease could be used as endpoints. Another factor is patient
compliance. Poor compliance may lead to variable or insufficient clinical response, which consequently results in lack
of separation from the placebo effect. Technologies to accurately monitor compliance are available, but the impact of
compliance on outcome is often ignored in clinical protocols. Considering the difficulties mentioned above, one does
not need to stress the importance of optimizing clinical trial design factors as much as possible, as to prevent failure
of clinical trials in depression for reasons other than true inefficacy of drugs.The pressure to overcome these hurdles
is high since antidepressant drugs are being developed by all major pharmaceutical companies. The need for novel
antidepressants is evident from the non-response rate of about 30%, which is observed for currently approved drugs,
and also from the multitude of side effects experienced by the target population. The high failure rate of clinical trials
has important consequences. Patients randomized to placebo in studies which fail to show a significant treatment
effect due to a false negative result are exposed to an ineffective treatment without accomplishing the ultimate goal
of clinical research, i.e., providing evidence of (absence of) benefit for the patient population. Also, clinical
development plans for antidepressant drugs suffer considerable delays due to such negative trials. In the most
extreme case, the development of efficacious drugs may be stopped, costing billions to the pharmaceutical industry
and most importantly, depriving depressed patients from better medication.
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CNS: Unleashing Opportunity
South East Asia: Landscape for Clinical Trial Expansion in CNS
For more than a decade, the emerging markets in South East Asia have held special promise for the global clinical research
industry. Driven by a combination of increased clinical research & GCP awareness, rapidly globalizing drug regulations,
technological innovations in healthcare, a talented workforce, improved access to the new medicines, better
physician-patient relationships and the rise of medical tourism, today these nations stand on the threshold to capture
majority of the clinical trial business from the developing world. In recent years, a veritable wave of Global MNCs have set
up shop in the entire South East Asian region and beyond, eager to capture a portion of the region’s comparative
advantages in talent costs, patient pools and disease demographics. Increasingly, a mixture of collaborative research,
contract research, outsourcing and co-development is sprouting all over South East Asia, fueled by Drug Development
organizations such as CROs/SMOs that are seeking to enhance revenue streams and expand market opportunities. A
flexible, global partner could prove to be a valuable ally in such a construct due to its efficient cost structure and regional focus.
Key Figures
India
India is home to more than 70 million population with major CNS disorders
More than 1500 active sites, hospitals in CNS with strong medical and IT infrastructure, using
English as the business language and thousands of ICH-GCP trained Psychiatrists (> 2000)
and Neurologists (> 1500) across 61 cities/towns.
High cost savings that can cut down CNS drug development costs by 50% to 60%
Shifting demographics favorable to CNS clinical research
Singapore
Over 15 % of the Singapore population suffering from major CNS disorders
More than 15 public/private specialist hospitals in CNS with strong medical and IT
infrastructure and over 100 Psychiatrists and over 50 Neurologists across the country
Malaysia
Approximately about 20 % of the Malaysian population affected with major CNS disorders
More than 15 specialty clinics in CNS with total number of Psychiatrists over 100; among those
32 were in private practice and total Number of Neurologists in Malaysia is more than 50
Thailand
The total number of human resources working in mental health facilities or private practice
is as follows: 419 psychiatrists; 2406 nurses; 163 psychologists; 465 social workers; 125
occupational therapists and 912 other health or mental health workers (including auxiliary
staff, non-doctor/non-physician primary health care workers, health assistants, medical
assistants, professional and paraprofessional psychosocial counselors) and total number of
neurologists is over 300.
Approximately about 25 % of the Malaysian population affected with major CNS disorders
Indonesia
The total number of Neurologists is around 300 and Psychiatrists are less than 500.
More than 20 % of the population are affected with major CNS disorders
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CNS: Unleashing Opportunity
MC SMO: Global Standards, Local Expertise
MC SMO provides the experience and resources to help sponsors overcome these obstacles and take advantage of the
opportunities in every phase of CNS Drug Development in South East Asia Region. MC SMO operates CNS Investigator
Site Network on five countries in South East Asia. This can help us to understand the local cultures, languages and logistics
to conduct clinical trials within a shorter duration, and consolidate our business strengths and bonding with KOLs across
the region. Some of our services include:
Trial Feasibility and Planning including Site/Investigator Identification, Selection, and Identifying Challenges related to the
Site Management/Patient Recruitment in CNS Drug Development and their Management
Proactive solutions to enroll suitable patients
Regulatory metrics and evidence provide scientific insights into advice on regulatory strategy or protocol with
established relationships with all the regulatory bodies in the region
Therapeutic Area Specific Training
Medical Consulting, Monitoring and Project Oversight related to Protocol and continuous on-going support
About MakroCare
MakroCare, a global drug development services organization, provides clinical
research, medical and consulting support to pharmaceutical, biotechnology and
medical device industries. The company offers project management, site
selection, patient recruitment, risk management, trial management (clinical and
late phase), clinical monitoring, CDM, quality assurance, medical writing,
Pharmacovigilance, biometrics, informatics and regulatory assistance.
MakroCare has offices in USA (New Jersey, Illinois, Pennsylvania and
California), India (Hyderabad, New Delhi, Mumbai and Bangalore), Japan
(Tokyo), Singapore and Europe (Frankfurt, Paris).
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