Clinical research in LMICs for TBI

1. Clinical research in LMICs
for TBI
Dr Amit Agrawal, MCh
Department of Neurosurgery
All India Institute of Medical Sciences
Saket Nagar
Bhopal 462020
Madhya Pradesh (India)

2. • TBI is the leading cause of morbidity, mortality and disability in young
adults
• It has been estimated that TBI costs the global economy approximately
$US400 billion annually
• Disproportionate burden of disability and death occurring in low-income
and middle-income countries (LMICs)
• Accurate estimates of TBI costs are scarce for many regions, and there is
wide variation in reported costs between available studies.
Global Burden of TBI
*Maas et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol.
2017 Dec;16(12):987-1048

3. LMICs face the greatest burden of trauma, as more than
70% of trauma-related deaths are estimated to occur
there
Mild TBI: 80%–90% of all TBI cases, are often not
reported or are underreported because very few of them
require hospitalization
Magnitude of Problem in LMIC

4. Magnitude of Problem in LMIC
2 million cases per year in LMIC DO NOT GET Essential Neurosurgical Care
and Services

5. Neurosurgical Randomized Trials in Low- and
Middle-Income Countries (n=397)*
HICs 73.3%
LMICs (n=106) 26.7%
China
Other LMICs
n=71
n= 35 (8.8%)
Patients enrolled
HIC-led trials
LMIC-led trials
A median of 92 patients
A median of 65 patients
Enrolling sites
HIC-led trials
LMIC-led trials
7.6 sites
1.8 sites
Over half (54.7%) of LMIC-led trials were institutionally funded
*Griswold DP, et al. Neurosurgical Randomized Trials in Low- and Middle-Income Countries. Neurosurgery. 2020 Sep
1;87(3):476-483. doi: 10.1093/neuros/nyaa049. PMID: 32171011; PMCID: PMC7426187

6. • High-quality research in high-income countries (HICs) but impact the majority
of populations in low-income and middle-income countries (LMICs).
• Disparity exists between countries with a high burden of TBI and those in which
most of the research is conducted
TBI Research in LMIC
*Tropeano MP, Spaggiari R, Ileyassoff H, Park KB, Kolias AG, Hutchinson PJ, Servadei F. A comparison of publication to TBI
burden ratio of low- and middle-income countries versus high-income countries: how can we improve worldwide care of TBI?
Neurosurg Focus. 2019 Nov 1;47(5):E5. doi: 10.3171/2019.8.FOCUS19507. PMID: 31675715

7. TBI Research in LMIC
• Between 2008 and 2018 a total of
8144 articles in the PubMed database
about TBI
• WHO regions AMR-US/Can with
4183 articles (51.36%)
• Almost 90 times lower than the ratio
of AMR-US/Can were the ratios for
AFR (1.15) and SEAR (0.46)
*Tropeano MP, Spaggiari R, Ileyassoff H, Park KB, Kolias AG, Hutchinson PJ, Servadei F. A comparison of publication to TBI burden ratio of low- and middle-income countries versus
high-income countries: how can we improve worldwide care of TBI? Neurosurg Focus. 2019 Nov 1;47(5):E5. doi: 10.3171/2019.8.FOCUS19507. PMID: 31675715

8. • Research from developing countries is under-represented in the empirical
literature*
• A retrospective bibliographic analysis of publications from 2015-2017 found only
4.52% of 6708 published reports had an LMIC affiliation**
TBI Research in LMIC
*Langer A, et al. Why is research from developing countries underrepresented in international health literature, and what can be done
about it? Bull World Health Organ2004;82(10):802-3. [published Online First: 2005/01/13]
*Servadei F, et al. Footprint of Reports From Low- and Low- to Middle-Income Countries in the Neurosurgical Data: A Study From
2015 to 2017. World Neurosurg2019;130:e822-e30. doi: 10.1016/j.wneu.2019.06.230 [published Online First: 2019/07/12]
*Kolias AG, et al. Traumatic brain injury: global collaboration for a global challenge. Lancet Neurol2019;18(2):136-37. doi:
10.1016/S1474-4422(18)30494-0 [published Online First: 2019/01/22]
**Servadei F, et al. Footprint of Reports From Low- and Low- to Middle-Income Countries in the Neurosurgical Data: A Study
From 2015 to 2017. World Neurosurg2019;130:e822-e30. doi: 10.1016/j.wneu.2019.06.230 [published Online First: 2019/07/12]

9. TBI Problem Overview: Case study from India
• Population of India: 1.33 billion
• Number of Annual TBIs: ~2 million people sustain traumatic brain injury (TBI)
each year
• Annual TBI Incidence: 160 cases of TBI/100,000 population (20 deaths/100,000
population)
• Prevalence: 94/100,000 population
• # of TBI procedures: ~180,000 annually
• Estimated total costs of road traffic injuries: about 55,000 crore a year
• Cause: 60% of TBIs happen due to road traffic accidents
• Age: Average age of hospitalization is 16–24 years
• Alcohol involvement is known to be present among 15%-20%
• Socioeconomic Breakdown: the majority of patients are low-middle income

10. • 362 medical colleges (both at government and private setup) only 59 have
neurosurgical departments recognized for MCh Neurosurgery training
program (190 candidate's intake per year)
• 1,800 neurosurgeons (one neurosurgeon for treating 25-30 lakh general
population)
• Out of a total 29 states and 7 union territories, only 20 states and 2
union territories have contributed in brain injury research
TBI literature: India

11. Agrawal A, et al. Traumatic brain injury related research in India: An overview of
published literature. Int J Crit Illn Inj Sci 2016;6:65-9

12. Agrawal A, et al. Traumatic brain injury related research in India: An overview of
published literature. Int J Crit Illn Inj Sci 2016;6:65-9

13. Agrawal A, et al. Traumatic brain injury related research in India: An overview of
published literature. Int J Crit Illn Inj Sci 2016;6:65-9

14. Area of Interest Frequency
Body Regions Involved 10
Clinical Presentation 17
Demographics 14
Follow up 8
Guidelines 2
Injury Pattern 5
Investigations 31
Management 15
Outcome 38
Prediction Model 5
Distribution of reporting variable in
publications (n=72)

15. • The examples from Latin America, China, and India and Nepal illustrate the
vast differences in the spectrum of neurotrauma research across LMICs
• Certain interventions may be high priority in one country, but low priority in
another.
• Outcome of TBI is often restricted at discharge from hospital and not
reported in structured form (often dichotomized as alive or dead; good or bad;
favorable or unfavorable)
• Neuropsychological outcome not addressed
• Prevalence of TBI in LMICs is similar to that of developed nations.
*Rubiano AM, Carney N, Chesnut R, Puyana JC. Global neurotrauma research challenges and opportunities. Nature. 2015 Nov 19;527(7578):S193-7. doi: 10.1038/nature16035. PMID:
26580327
*Khan A, Prince M, Brayne C, Prina AM. Lifetime Prevalence and Factors Associated with Head Injury among Older People in Low and Middle Income Countries: A 10/66 Study. PLoS
One. 2015 Jul 6;10(7):e0132229. doi: 10.1371/journal.pone.0132229. PMID: 26146992; PMCID: PMC4493012
Challenges

16. • Unfortunately, the evidence generated from neurotrauma studies carried
out in high-income countries does not always translate to LMICs, where
the health infrastructure (including providers and facilities) is limited,
creating a different context for care practice*
• Recently published consensus statements, established in high-income
countries, do not take into account the unique challenges that
neurotrauma researchers may face in LMICs. Most of these evidence-
based recommendations are best applied in well-funded and well-
equipped neurosurgical or neurotrauma centres**
Challenges
*Gosselin, R. A. The increasing burden of injuries in developing countries. Direct and indirect consequences. Tech. Orthop. 24, 230–232 (2009)
*Borse, N. N. & Hyder, A. A. Call for more research on injury from developing world: results of a bibliometric analysis. Indian J. Med. Res. 129, 321–326 (2009)
*Sitsapesan, et al. Neurotrauma outside the high-income setting: a review of audit and data collection strategies. World Neurosurg. 79, 568–575 (2013)
**Rubiano, A. M. & Rios, A. M. Neurotrauma research in Latin America. J. Res. Fund. Care Online 6, 1–2 (2014).
**Razmkon, A. Priorities and concerns for research on neurotrauma in the developing world. Bull. Emerg. Trauma 1, 5–6 (2013).
**Rubiano, A. M. Strengthening neurotrauma care in the Pan American Region. J. Trauma Crit. Care Emerg. Surg. 2, 5–6 (2013).

17. • Delayed presentation
• Under investigation (poor affordability and lack of medical insurance)
• Treatment may be appropriate but sometime suboptimal
• Inadequate follow up data
• Patients who need rehabilitation : 1.5 million / year
• Less than 10 integrated dedicated multidisciplinary inpatient
neurorehabilitation facilities in country
• Long term neuro-rehabilitation services available: Not enough to provide
optimum care and to all those who need it
Challenges

18. Future
• It will take substantial effort, time, and funds to conduct high-volume and quality
sophisticated research originating from LMICs
• There is a need to encourage investigators from HICs to collaborate with colleagues
from LMICs to improve their research capacity and guide-line production
• Call for improvement of data collection and research outputs along with an increase
in international collaboration could quantitatively and qualitatively improve the ability
of LMICs to ameliorate TBI care and develop clinical practice guidelines.
• Development, validation, and implementation of prognostic models in TBI,
particularly for less severe TBI.
(Tropeano MP, Spaggiari R, Ileyassoff H, Park KB, Kolias AG, Hutchinson PJ, Servadei F. A comparison of publication to TBI burden ratio of low- and middle-
income countries versus high-income countries: how can we improve worldwide care of TBI? Neurosurg Focus. 2019 Nov 1;47(5):E5. doi:
10.3171/2019.8.FOCUS19507. PMID: 31675715)

19. Clinical Care, Prevention and Research are
Interdependent
Translation from
basic science to
human studies
Translation of
new knowledge
into clinical practice
Basic
Research
Clinical
Research
Improved
Health
Adapted from Sung et al. (2003) JAMA, 289, 1278-89.
Copyright © (2003) American Medical Association. All Rights reserved.

20. • Cooperation among a diverse group of stakeholders—including research
sponsors (industry, academia, government, nonprofit organizations, and
patient advocates), clinical investigators, patients, payers, physicians, and
regulators—is necessary in conducting a clinical trial today
• Majority of the research is focused on the most effective clinical
interventions for managing TBI, mild cases are missing
Challenges in clinical research
Narayan, Raj K et al. “Clinical trials in head injury.” Journal of neurotrauma vol. 19,5 (2002): 503-
57. doi:10.1089/089771502753754037

21. Conclusions
• This multitude of challenges in TBI—encompassing systems of care,
clinical management, and research strategy
• The quality of reporting of quantitative studies published on TBI from
LIMC is largely inadequate
• Considering the growing impact of TBI on health resources in LMICs,
there is an urgent need for further research.
• Need for a consensus to identify needs and limitations in research in
LMICs to have right research questions?