THE GENDER PERSPECTIVE IN DRUG DESIGNING AND DEVELOPMENT PROCESSES- A REVIEW
Keywords:Drug Development Processes, Sex and Gender Perspective, Challenges
It has long been assumed that females have the same response as males to the drugs in all the five phases of drug development processes namely drug discovery & development, preclinical trials, clinical trials, drug review and drug marketing. The fact is that the diseases exhibit the potential sex difference in its prevalence, diagnosis, severity and outcomes. Diseases like breast cancer, urinary tract infections affect men and women differently. The difference also exits in the manifestation of the diseases like cardiovascular disease and sexually transmitted diseases. The differences of the sex are further widened by the gender perspective. Gender is one of the fundamental determinants of health inequalities. There are differences in the physiology of the sexes that causes difference in the pharmacodynamics for specific drug which can be due to the circulating levels of endogenous hormones such as testosterone and estradiol. Women typically have a lower bodyweight than men, so when taking the same dose of a drug results in higher level of drug. Lyophilic agents may have a larger distribution in females owing to their higher body fat content. Women may experience different health issues due to cultural, social and economical factor and hence it becomes an issue related to gender bias.Their is a need to examine the potential difference by sex at all the life stages at all the levels, like genetic and cellular level to organism level. Also there is a need to take into consideration this sex difference in all the stages of the drug development, pre-clinical and clinical trial. It has been observed that while studying diseases prevalent in both the sexes only male animals were considered to be norm study population. It was assumed that female would have same response as males during the pre-clinical trials and that women will have same response as men from drugs in the clinical trials. The assumption of equality puts women at risk, not only reducing disease treatment efficacy but also risking exposure to unforeseen side effects. Women have been viewed as more expensive test subjects because of their more fluctuating hormone levels. It has to take the possible hormonal interaction into consideration during the pharmacodynamics, pharmacokinetics when it comes to determine the safety, efficacy and tolerance of new drugs. Although there have been lack of representation of women in clinical trials initially due to non availability of data that the potential sex differences exist but now guidelines, policies and organizations have been established to increase the quality of women's health research. In 1993, the National Institute of Health Revitalization Act came into being to promote inclusion of women in clinical trials. The acceptance that sex differences should be considered while taking clinical decisions itself proves that there has been a major breakthrough but a lot is to be done. The studies on cardiovascular disease pattern for males and females creates awareness and the governments are making policies and guidelines for the gender specificity in the drug designing and development processes and strict enforcement during the approval processes. There is along way to go.
Arnold, A.P. Mouse Models for Evaluating Sex Chromosome Effects That Cause Sex Differences In Non-Gonadal Tissues. J. Neuroendocrinol. 21, 2009, 377–386. DOI: https://doi.org/10.1111/j.1365-2826.2009.01831.x
Arnold, A.P. Promoting The Understanding Of Sex Differences To Enhance Equity And Excellence In Biomedical Science. Biol. Sex Differ. 2010, 1. DOI: https://doi.org/10.1186/2042-6410-1-1
Arnold, A.P., And Burgoyne, P.S. Are XX and XY Brain Cells Intrinsically Different? Trends Endocrinol. Metab. 15, 2004, 6–11. DOI: https://doi.org/10.1016/j.tem.2003.11.001
Arnold, A.P., And Chen, X. What Does The ‘‘Four Core Genotypes’’ Mouse Model Tell Us About Sex Differences In The Brain And Other Tissues? Front. Neuroendocrinol. 30, 2009, 1–9. DOI: https://doi.org/10.1016/j.yfrne.2008.11.001
Beierle I, Meibohm B, Derendorf H. Gender Differences in Pharmacokinetics And Pharmacodynamics. Int J Clin Pharmacol Ther. 1999;37(11):529–547.
Bekhouche, Y.H.R., Tyson, L.D., And Zahidi, S. The Global Gender Gap Report, 2015 (World Economic Forum).
Bhatt A. Clinical Trials In India: Pangs Of Globalization. Indian J. Pharmacol. 36(4), 2004, 207 -08.
Bozkurt B1, Khalaf S1. Heart Failure in Women. Methodist Debakey Cardiovasc J. 2017 Oct-Dec; 13(4):216-223.
Cambronero Saiz B, Ruiz Cantero MT, Papi Galvez N. Quality of Pharmaceutical Advertising and Gender Bias In Medical Journals (1998–2008): A Review Of The Scientific Literature. Gac Sanit. 2012;26: 469–76. DOI: https://doi.org/10.1016/j.gaceta.2011.11.002
Clayton JA1, Arnegard ME1. Taking Cardiology Clinical Trials to The Next Level: A Call to Action. Clin Cardiol. 2018 Feb; 41(2):179-184. Doi: 10.1002/Clc.22907. Epub 2018 Feb 26. DOI: https://doi.org/10.1002/clc.22907
Collins, P., Stevenson, J.C., And Mosca, L. Spotlight On Gender. Cardiovasc. Res. 53, 2002, 535–537. DOI: https://doi.org/10.1016/S0008-6363(02)00224-9
Cooper, G.S., And Sandler, D.P. Age At Natural Menopause And Mortality. Ann. Epidemiol. 8, 1998, 229–235. DOI: https://doi.org/10.1016/S1047-2797(97)00207-X
Dai, W., Li, Y., And Zheng, H. Estradiol/ Testosterone Imbalance: Impact On Coronary Heart Disease Risk Factors in Postmenopausal Women. Cardiology 121, 2012, 249–254. DOI: https://doi.org/10.1159/000337274
Gulati M, Shaw LJ, Bairey Merz CN. Myocardial Ischemia In Women: Lessons From The NHLBI WISE Study. Clin Cardiol. 2012;35: 141–148. DOI: https://doi.org/10.1002/clc.21966
Gupta V, C. Mohan Reddy, K. Pradeep Reddy, R. Ajay Kulkarni, H.G. Shivakumar. Process of Approval of New Drug in India with Emphasis on Clinical Trials. Volume 13, Issue 2, March – April 2012; Article-004 ISSN 0976 – 044X, International Journal of Pharmaceutical Sciences Review and Research.
Harris DJ, Douglas PS. Enrollment of Women in Cardiovascular Clinical Trials Funded by The National Heart, Lung, And Blood Institute. N Engl J Med 2000;343: 475-80 DOI: https://doi.org/10.1056/NEJM200008173430706
Hausmann, R., Tyson, Laura D., And Zahidi, S. The Global Gender Gap Report, 2012 (World Economic Forum).
Herz S. Don't Test, Do Sell: Legal Implications of Inclusion of Women In Clinical Drug Trials. Epilepsia. 1997;38(Suppl 4):S42–9. DOI: https://doi.org/10.1111/j.1528-1157.1997.tb04538.x
Honorio S. Phases of Drug Development; Good Practices In Clinical Research. Available At: Www.Hstelearning.Mit.Edu. Accessed On Feb 26, 2019
Holdcroft A. Gender Bias in Research: How Does It Affect Evidence Based Medicine? Pharm Pract(Granada) 2016 Jan-Mar; 14(1): 708. Published Online 2016 Mar 15.
Izadnegahdar, M., Singer, J., Lee, M.K., Gao, M., Thompson, C.R., Kopec, J., And Humphries, K.H. Do Younger Women Fare Worse? Sex Differences in Acute Myocardial Infarction Hospitalization and Early Mortality Rates Over Ten Years. J. Womens Health 23, 2014, 10–17 DOI: https://doi.org/10.1089/jwh.2013.4507
Jacobsen, B.K., Nilssen, S., Heuch, I., And Kva ̊ Le, G. (1997). Does Age at Natural Menopause Affect Mortality From Ischemic Heart Disease? J. Clin. Epi- Demiol. 50, 475–479. DOI: https://doi.org/10.1016/S0895-4356(96)00425-8
Jankowska, E.A., Rozentryt, P., Ponikowska, B., Hartmann, O., Kustrzycka-Kratochwil, D., Re- Czuch, K., Nowak, J., Borodulin-Nadzieja, L., Po- Lonski, L., Banasiak, W., Et Al. Circulating Estradiol And Mortality In Men With Systolic Chronic Heart Failure. JAMA 301, 2009, 1892–1901. DOI: https://doi.org/10.1001/jama.2009.639
Kannel, W.B., And Wilson, P.W. Risk Factors That Attenuate the Female Coronary Disease Advan- Tage. Arch. Intern. Med. 155, 1995, 57–61. DOI: https://doi.org/10.1001/archinte.155.1.57
Katherine A. Liu and Natalie A Dipietro Mager. Women’s Involvement in Clinical Trials: Historical Perspective and Future Implications. 2016 March, 15, Pharm Pract.
Kawachi I, Kennedy B, Gupta V, Prothow-Stith D. Women's Status and The Health of Women and Men. Soc Sci Med. 1999; 48:21–32. DOI: https://doi.org/10.1016/S0277-9536(98)00286-X
Kuhlmann J, Alternative Strategies in Drug Development: Clinical Pharmacological Aspects. Int. J. Clin. Pharmacol. Ther. 37(12), 1999, 575-83.
Lachman L, Liberman HA, Kanig JL, The Theory and Practice of Industrial Pharmacy, Varghese Publishing House, 3rd Edition 1987. 856-82.
Larosa J, Pinn VW. Gender Bias in Biomedical Research. J Am Med Womens Assoc. 1993; 48:145–51.
Lippman A. The Inclusion of Women In Clinical Trials: Are We Asking The Right Questions? Women and Health Protection. 2006. Available From:
Merkatz RB, Junod SW. Historical Background of Changes In FDA Policy On The Study And Evaluation Of Drugs In Women. Acad Med. 1994; 69:703–7. DOI: https://doi.org/10.1097/00001888-199409000-00004
Miller M. Gender Differences in The Toxicity of Pharmaceuticals- The Food And Drug Administration’s Perspective. Int J Toxicol. 2001; 20(3):149–152. DOI: https://doi.org/10.1080/109158101317097728
NIH Guidelines On the Inclusion of Women and Minorities As Subjects In Clinical Research (1994) 59 Fed. Reg. 14508-14513
Sanghavi M, Rutherford JD. Cardiovascular Physiology of Pregnancy. Circulation. 2014;130: 1003–1008. DOI: https://doi.org/10.1161/CIRCULATIONAHA.114.009029
Schwarcz, M.D., And Frishman, W.H. Testosterone and Coronary Artery Disease. Cardiol. Rev. 18, 2010, 251–257. DOI: https://doi.org/10.1097/CRD.0b013e3181e84673
Skafar, D.F., Xu, R., Morales, J., Ram, J., And Sowers, J.R. Clinical Review 91: Female Sex Hormones and Cardiovascular Disease In Women. J. Clin. Endocrinol. Metab. 82, 1997, 3913–3918.Sozzi, DOI: https://doi.org/10.1210/jcem.82.12.4443
F.B., Danzi, G.B., Foco, L., Ferlini, M., Tu- Baro, M., Galli, M., Celli, P., And Mannucci, P.M. Myocardial Infarction in The Young: A Sex-Based Comparison. Coron. Artery Dis. 18, 2007, 429–431. DOI: https://doi.org/10.1097/MCA.0b013e3282583bfc
Soderstrom M. Why Researchers Excluded Women from Their Trial Populations. Lakartidningen 2001;98: 1524-8
Sullivan S, Hammadah M, Al Mheid I, Et Al. Sex Differences In Hemodynamic and Microvascular Mechanisms Of Myocardial Ischemia Induced By Mental Stress. Arterioscler Thromb Vasc Biol. 2018;38: 473–480. DOI: https://doi.org/10.1161/ATVBAHA.117.309535
Parekh A, Fadiran E, Uhl K, Throckmorton D. Adverse Effects in Women: Implications For Drug Development And Regulatory Policies. Expert Rev Clin Pharmacol. 2011; 4(4): 453–466. Doi:10.1586/Ecp.11.29. DOI: https://doi.org/10.1586/ecp.11.29
Pagidipati NJ, Peterson ED. Acute Coronary Syndromes in Women and Men. Nat Rev Cardiol. 2016; 13:471–480. DOI: https://doi.org/10.1038/nrcardio.2016.89
Ravinder RB & Suresh N, Regulatory Stages for New Drug Approvals. Available At Www.Observerindia.Com/Cms/Export/Orfonline/Modules/Occasionalpaper/Attachments/Drug_Discovery_Book_1 260179432814.Pdf. Accessed On Oct 20, 2019.
Regensteiner JG, Golden S, Huebschmann AG, Et Al; American Heart Association Diabetes Committee Of The Council On Lifestyle And Car- Diometabolic Health, Council On Epidemiology And Prevention, Council On Functional Genomics And Translational Biology, And Council On Hypertension. Sex Differences In The Cardiovascular Consequences Of Diabetes Mellitus: A Scientific Statement From The American Heart Association. Circulation. 2015;132: 2424–2447. DOI: https://doi.org/10.1161/CIR.0000000000000343
Ren, J., And Kelley, R.O. Cardiac Health In Women With Metabolic Syndrome: Clinical Aspects And Pathophysiology. Obesity (Silver Spring) 17, 2009, 1114–1123. DOI: https://doi.org/10.1038/oby.2009.8
Rochon PA, Clark JP, Binns MA, Patel V, Gurwitz JH. Reporting of Gender-Related Information In Clinical Trials Of Drug Therapy For Myocardial Infarction. CMAJ 1998;159: 321-7 [PMC Free Article] [Pubmed]
Ruiz M, Verbrugge L. A Two Way View Of Gender Bias In Medicine. J Epidemiol Community Health. 1997; 51:106–9. DOI: https://doi.org/10.1136/jech.51.2.106
Ruiz-Cantero MT, Vives-Cases C, Artazcoz L, Delgado A, García Calvente Md M, Miqueo C. A Framework to Analyse Gender Bias In Epidemiological Research. J Epidemiol Community Health. 2007;61(Suppl 2): Ii46–53. DOI: https://doi.org/10.1136/jech.2007.062034
Vaccarino V, Wilmot K, Al Mheid I, Et Al. Sex Differences In Mental Stress–Induced Myocardial Ischemia In Patients With Coronary Heart Disease. J Am Heart Assoc. 2016;5: E003630. DOI: https://doi.org/10.1161/JAHA.116.003630
Varkey P, Kureshi S, Lesnick T. Empowerment of Women and Its Association with The Health of The Community. J Womens Health. 2010; 19:71–6. DOI: https://doi.org/10.1089/jwh.2009.1444
Weisz D, Gusmano MK, Rodwin VG. Gender and The Treatment of Heart Disease In Older Persons In The United States, France, And England: A Comparative, Population-Based View Of A Clinical Phenomenon. Gend Med. 2004;1: 29-40 DOI: https://doi.org/10.1016/S1550-8579(04)80008-1
Westerman S1, Wenger NK2. Women And Heart Disease, The Under-recognized Burden: Sex Differences, Biases, And Unmet Clinical And Research Challenges. Clin Sci (Lond). 2016 Apr;130(8):551-63. Doi: 10.1042/CS20150586. DOI: https://doi.org/10.1042/CS20150586
Wizemann TM And Pardue ML. Understanding The Biology Of Sex And Gender Differences, Exploring The Biological Contributions To Human Health; Does Sex Matter? National Academic Press (US) 2001,2 Every Cell Has a Sex.
Woosley R. From Benchside to Bedside: Role of Gender-Based Therapeutics In The Clinical Care Of Women. J Womens Health. 1998;7(1):21–23. DOI: https://doi.org/10.1089/jwh.1998.7.21
Westerman S, Wenger NK. Women and Heart Disease, The Under-Recognized Burden: Sex Differences, Biases, And Unmet Clinical And Research Challenges. Clin Sci (Lond). 2016;130: 551–563. DOI: https://doi.org/10.1042/CS20150586
Yanes, L.L., And Reckelhoff, J.F. Postmenopausal Hypertension. Am. J. Hypertens. 24, 2011, 740–749. DOI: https://doi.org/10.1038/ajh.2011.71
Zhang Z, Hayward MD. Gender, The Marital Life Course, And Cardio- Vascular Disease In Late Midlife. J Marriage Fam. 2006; 68: 639–657 DOI: https://doi.org/10.1111/j.1741-3737.2006.00280.x
How to Cite
License and Copyright Agreement
In submitting the manuscript to the journal, the authors certify that:
- They are authorized by their co-authors to enter into these arrangements.
- The work described has not been formally published before, except in the form of an abstract or as part of a published lecture, review, thesis, or overlay journal.
- That it is not under consideration for publication elsewhere.
- That its release has been approved by all the author(s) and by the responsible authorities – tacitly or explicitly – of the institutes where the work has been carried out.
- They secure the right to reproduce any material that has already been published or copyrighted elsewhere.
- They agree to the following license and copyright agreement.
Authors who publish with International Journal of Engineering Technologies and Management Research agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License (CC BY-SA 4.0) that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors can enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or edit it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) before and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.
For More info, please visit CopyRight Section