A Review on Personalized Medicine

1.????Introduction

1.1 General Concept

Personalized medicine is a new era in medical science. In accordance with each patient's anticipated response or risk of illness, a medical model known as Personalized medicine, also referred to as precision medicine, divides people into distinct groups. Then, specific medical decisions, procedures, therapies, and/or products are tailored for each patient. According to National Human Genome Research Institute, “Personalized medicine, which examines a person's genetic profile to guide decisions regarding illness prevention, diagnosis, and treatment, is an emerging field of medicine. Doctors can select the finest medication and provide it with the proper dosage or regimen in a patient’s genetic profile file of a patient. Data from the Human Genome Project is being utilized to improve individualized care.” [NHGRI, 2022].

Some other terms describe personalized medicine [Vogenberg et al., 2010]:

·????????Precision medicine

·????????Stratified medicine

·????????Targeted medicine

·????????Pharmacogenomics

The subject of personalized medicine is projected to substantially influence clinical practice as novel applications continue to gain acceptance. The advancement of genome-based tools to analyze variation at the DNA, RNA, protein, and metabolite levels is largely responsible for the enthusiasm around personalized medicine [Sorich and Mckinnon, 2012]. Numerous genomic applications that support medical judgment and enhance health outcomes are now in use in the clinic. The Personalized medicine movement is particularly focused on pharmacogenetic (PGx) testing, or assessments of the possibility or risk of adverse medication reactions [Sorich and Mckinnon, 2012].

Personalized medicine has great promise, and new clinical tests are constantly being developed, but these techniques have been slowly adopted into daily practice. The absence of clinical usefulness proof, physician ignorance, patient interest, insurance coverage, and reimbursement are probable contributing factors to delayed acceptance [Speaer et al., 2015]. When determining medical coverage policies for insurance, several elements are taken into account, such as the overall strength of the evidence for a particular test, the accessibility of clinical guidelines, their current usage by doctors, patient interest, and cost-effectiveness. Each of these parameters has clinical usefulness data supporting it. It seems sensible that payers are hesitant to pay for a test that might not significantly influence the choices and results of a patient's treatment. However, other factors, such as physician usage, may outweigh the lack of data indicating therapeutic usefulness [Gebhart et al., 2018].

A "one size fits all" method of diagnosis, treatment, and prevention may be changed into a personalized one using Personalized medicine. We are all unique, for sure, but we are also all the same. And if there is anything more correct than making a blind purchase at a shoe store without first ascertaining the size, it is the idea that medicine would be done in a way that disregards such variances. The emergence of Personalized medicine is being significantly influenced by genomics, which provides a very specific molecular window into those differences between us and allows us to make individualized predictions about disease risk, which can help someone choose the best prevention strategy for them. Instead of employing a "one size fits all" approach to drug management, in certain situations it also enables the selection of the best prescription at the optimal dosage for the appropriate patient. It will eventually be impossible to see how any field of medicine would be unaffected by this as we learn more about each individual and as more people become aware that our complete genomes are being sequenced and uploaded to our medical records to facilitate that kind of personalized approach. But, this might be the biggest medical revolution in a very long time. There is still work to be done [NHGRI, 2022].

1.2 ?Importance of Personalized medicine

History has seen a large amount of reactive medical practice. Even today, we usually have to wait for the symptoms of an illness to appear before we try to treat or cure it. Additionally, because we are still learning about the genetic and environmental factors that influence the develoPersonalized medicineent of serious diseases like cancer, Alzheimer's, and diabetes, our efforts to treat them are usually irregular, unexpected, and ineffective which is shown in Figure 1.1.

We test the drugs and treatments we create on sizable populations, and then we make recommendations based on statistical averages. As a result, due to population genetic variations, they work for some people but not for many. Now on the market, the average prescription drug only benefits 50% of its users [Jackson Laboratory, 2018].

1.3 Benefits of Personalized Medicine

1.3.1 Patients Make Informed Decisions

Because of customized medicine, a patient's reaction to certain treatments, exercises, and medications may be anticipated with a great lot of precision. Patients who take part in decision-making are more likely to stick to their treatment programs and make informed health decisions. Many people with chronic illnesses regularly express the opinion that their illness has taken away their power. Through individualized care, patients regain control and may take an active role in their own health [David, 2019].

1.3.2 Increases Patient Engagement

Patients are more engaged with their treatment plan when they receive more tailored information that enables them to make better health decisions. Other advantages of patient participation include improved patient outcomes, increased financial gain for healthcare providers, and improved patient-therapist relationships. High levels of patient involvement and activation increase the likelihood that patients will continue their physical therapy program. Patient activation measures how well-informed, competent, and confident a patient is in managing their health [David, 2019].

1.3.3 Higher Probability of the Desired Outcomes

High-quality, individualized care and extensive patient involvement directly contribute to better patient outcomes. As customized therapy adapts as the patient heals, patients are more likely to comply with treatment and achieve better outcomes. It could even hasten their recovery. In a sector where expenses are always growing, patients are more inclined to stick with their healthcare provider if they receive the outcomes they were hoping for. Patients and providers will develop a strong bond if patients are happy with their results. Because of this, patients and medical professionals gain from customized medicine [Trosman et al., 2016].

1.3.4 Focus on Preventative Medicine?

Preventative care is receiving more attention as a result of the medical industry's transition to value-based individualized treatment. Patients can live better lives and prevent certain illnesses because of this shift from reactive to proactive care. Preventative care can lower a patient's overall medical costs and enable therapists and healthcare professionals to treat them more successfully. Through education, direct intervention, and integrative therapies, physical therapy in particular can help patients avoid treatable health issues, leading to a better and happier life [Cronin et al., 2014].

1.3.5 Reduce Costs for Patients?

As preventative treatment and maintenance are less expensive than treating chronic illnesses or diseases like cancer, Personalized medicine is more cost-effective than traditional methods of healthcare. The long-term advantages greatly surpass the early expenses, which may appear higher than the expenditures associated with the disease. Also, it improves the quality of life for people with crippling illnesses [David, 2019].

1.4 Drawbacks of Personalized Medicine

·????????The response to medication may be a result of the interactions of multiple genes.

·????????The exchange of data and ethical concerns with genetic testing.

·????????Doctors typically lack knowledge of the tests that are available, the medicines that go along with them, and the results.

·????????The reimbursement pathway of testing does not establish.

2.????Personalized medicine in Bangladesh

In the concept of Bangladesh, Personalized medicine is a very new concept. But in terms of Bangladesh, it is a very important idea. There are many side effects due to the use of an excessive amount of medicine like antibiotic resistance, kidney and heart problem, insomnia, etc.

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2.1 Antibiotics Resistance

Because many people in Bangladesh are in high danger of antibiotic-resistant, many types of antibiotics in the Pharma market may be sold without any prescription. It can be determined by the market size of antibiotics. According to the IMS 4Q22, antibiotics are the most sold medicines after PPI (Proton Pump Inhibitor) in Bangladesh which is shown in Table 2.1.

Table 2.1: Antibiotic Pharma Market [IMS 4Q22, 2023]

Antibiotic Name

Market Size (Cr.)

Amoxicillin + Clavulanic Acid

194.9

Cefuroxime Axetil + Alavulanic Acid

692.18

Fluconazole

116.0

Cefixime

689.88

Amoxicillin +Clarithromycin + Lansoprazole

14.2

Due to the use of excessive amounts of antibiotics, they are high resistance to antibiotics. According to the Directorate General of Drug Administration, Antibiotic result in the death of about 3,500 people every day. Around 1.2 million individuals passed away in 2019 as a direct result of antibiotic-resistant bacterial infections, according to research published in the medical journal Lancet early this year. Perhaps millions more people died [The Daily Star, 2023].

2.2 Kidney Disease

Non-Steroidal Anti-inflammatory Drug which is popular in our country, all of those medicines are nonselective COX inhibitor. COX-2 is responsible for pain, on the other hand, COX-1 maintains gastric safety, platelet aggregation, etc. Popular NSAIDs (Non-Steroidal Anti Inflammatory Drugs) which are available in the market are nonselective COX inhibitors. As a result, it may cause gastric problems and platelet aggregation which hamper cardiac and kidney patients. So Personalized medicine is needed in this condition. The market size of NSAIDs is given in Table 2.2 which indicates the highest sales of NSAIDs product. To reduce this type of disease, the use of Personalized medicine is very important.

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Table 2.2: NSAIDs Pharma Market [IMS 4Q22, 2023]

NSAID Name

Market Share (Cr.)

Esomeprazole + Naproxen

292

Nabumetone

132

Etoricoxib

129.9

2.3 Availability of Personalized medicines

Some medicals are starting their journey with Personalized medicine, especially in the oncology department.

? Square Hospital

? Evercare hospital

? Labaid Hospital

2.4 Scope of Personalized medicine in Bangladesh

Giving each patient the best care and results is the ultimate objective of customized medicine. Genetic technology may be applied at a number of critical points along the continuum from health to illness. pharmacogenetic therapy aims to increase the likelihood of a positive response, decrease response heterogeneity, lower the risk of side effects and/or serious adverse effects, and prolong the marketing exclusivity period.

Each patient's intrinsic susceptibility, intrinsic morbidity, extrinsic susceptibility, and extrinsic morbidity are the four factors that personalized medicine encourages. Genetics, family history, and genetic information affected intrinsic susceptibility. Morbidity takes into account each person's unique reaction to illness. Smoking and air pollution are two examples of environmental variables that increase a person's vulnerability to illness. Because of insufficient medical care, poverty, and other circumstances, the morbidity of one disease worsens for those who suffer another condition. Family history; evaluation of a family medical history would reveal those who are at high risk for sickness (e.g., by family), allowing for both therapeutic and preventative treatments. Genome-based health testing, clinical decision support systems, and assessments of the risk of chronic diseases may all be used to make decisions on clinical diagnosis and prognosis, risk forecasting, carrier screening, and clinical therapy.

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Advantages of personalized medicine

? Increases the chances of a doctor to use the patient’s genetic and molecular information.

? Enhances the ability to predict the best treatment for a specific patient

? It improves the ability to understand the underlying mechanisms of the disease.

? It helps in preventing, diagnosing and treating a range of diseases.

Disadvantages of personalized medicine

? Huge data needs to be collected from the patient

? The patient has to be aware of the family history

? Time-consuming

3.????Personalized medicine

3.1 Types of Personalized medicine

·????????Genomic Medicine: The use of genetic information in clinical settings and its consequences on patient outcomes and policy are investigated by the rapidly expanding branch of medicine known as genomic medicine (e.g., for diagnostic or therapeutic decision-making). Genomic medicine is already making a difference in the fields of cancer, pharmacology, unusual and undiagnosed ailments, and infectious diseases [NHGRI, 2022].

·????????Precision Medicine: Modern approaches to sickness prevention and treatment include precision medicine. It will allow medical practitioners and researchers to predict which medicines are more likely to be beneficial for a certain patient by taking into account that patient's particular genetic and molecular make-up, environment, and lifestyle [AstraZeneca, 2022].

·????????Tailored Medicine: Precision, customized, and even genomic medicine have all been used to refer to tailored healthcare. To design (or adapt) a treatment plan for your ailment, it takes into account your genetic information, lifestyle, and environment [Webmed, 2021].

·????????Preventive Approach: Preventative methods are any actions a teacher takes to put an end to undesirable behavior. Instead of waiting for problem behaviors to occur, proactive tactics that are employed effectively lower the likelihood of these behaviors and promote healthy behavioral choices in the classroom.

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3.2 Personalized medicine for Cancer Patients

Ovarian cancer, widely known as the "silent killer," is now being treated with personalized therapy as more than 80% of women who are diagnosed with it do so at a late stage and have a dismal prognosis. The biology of these tumors is highly complicated, which poses one difficulty in the treatment of ovarian cancer. Because each ovarian tumor has a unique underlying Genetic alteration (mutation), each patient's tumor is unique. How the patients respond to therapy is consequently determined by these mutations.?

3.2.1 “Reading” the Genetic Makeup of a Tumor to Identify Drugs that Target Mutations Found within the Tumor

Cancer therapy decisions have been made for many years depending on the tumor histology of the patient. In other words, pathologists examine a small sample of a patient's tumor under a microscope and classify it based on, say, how cancer cells differ from normal cells in appearance. There are several histological subtypes of ovarian cancer, and each one reacts differently to conventional treatment. We now know through study that these subtypes are caused by various underlying genetic variations (mutations). Clinical investigation is now being conducted to ascertain the genetic composition of a patient's tumor and spot alterations within it [Cancer Genomics Program Clinical Trial Studies, 2020]. Genetic profiling, or scanning the tumor's DNA, offers the possibility of finding medications that target the tumor's mutations only. In the future, a blood sample may also be used to get the DNA from the tumor biopsy. For doctors and cancer researchers, knowing a patient's cancer changes is extremely helpful. Genetic profiling has aided in improving outcomes in some malignancies when the mutations are well-characterized, thanks to the oncologists' better-educated choice of therapies. For instance, chemotherapy normally works significantly better for ovarian cancer patients who have the hereditary type of disease and carry a mutation in their BRCA genes. In this same group of patients, researchers are also looking into the medicine olaparib. Further genetic variations related to this disease may become significant targets for ovarian cancer treatment when more targeted medications for the disease are authorized.

3.2.2 Mouse Avatars to Determine Treatment Options

Oncologists are exploring innovative methods to test many prospective treatment plans on a patient’s tumor in order to determine which one is best for that particular patient. For instance, by cultivating patient tumor cells in a Petri dish, researchers have tested medications on human subjects. Unfortunately, the majority of cancer cells do not endure these circumstances. Growing fragments of a patient’s tumor in mice is a more effective and popular method. Several businesses have already started supplying patients in the US with this technique. This method involves surgically removing a bit of the tumor from the patient and implanting it under the skin of several mice, where it can develop. The mice with tumors are treated with both conventional therapies and prospective novel medications, and then the results are compared. It is thought that a medicine may be successful in a patient if it causes the tumor to shrink in mice when administered to them. Patients with ovarian cancer have previously benefited from this strategy. This approach hasn’t been tested on humans in randomized clinical trials, despite looking promising.

3.2.3 Challenges of Personalized medicine

In spite of these achievements, customized medicine is facing new difficulties. For instance, the method is rather expensive in both of the cases I gave. Using numerous mice for a single patient to test various medications or sequencing a patient's tumor and analyzing the data might cost thousands of dollars. However, not all cancer changes (mutations) will be targeted by cancer medications, and it's likely that over time, the cancer cells could develop treatment resistance. In order to forecast the most effective course of therapy for patients, Personalized medicine has a lot of potentials, and researchers are constantly developing new techniques, such as nanotechnology. Without sequencing the tumor DNA or using animal models, these recently developed diagnostics may be able to identify which patients with ovarian cancer would react to chemotherapy or targeted therapy. For diseases like ovarian cancer to be treated with customized medicine as a regular practice, further research is required. I think tailored cancer treatment has a promising future and will provide ovarian cancer patients with potent therapeutic alternatives.

3.3 ?Personalized medicine for Cardiovascular Disease

The application of genetic data to inform medical decision-making is one approach to defining?genomics. The human genome sequences, gene expression patterns, proteome, and metabolize were postulated.?The about 10-15 million CNVs, SNPs, and whole-genome sequences that make up the human genome are the subject of genomic research. Transcriptomics, or genome-wide analysis of RNA expression, includes a variety of elements, such as messenger RNA and non-coding RNAs (small interfering RNA, and microRNAs). However, because miRNAs lack selectivity, their study of them can be challenging. Transcriptome analysis uses RNA sequencing. The study of proteins is known as proteomics, and the proteome is the totality of all known proteins and all of their numerous varieties. It continues to be a top focus in the field of molecular and biomarker medicine. According to one definition, biomarkers are pharmacological reactions to therapeutic treatments or quantitatively measurable indications of either beneficial or detrimental biological processes [Clin Pharmacol Ther.?2001]. They may appear as genes, proteins, carbohydrates, radioactively-tagged materials, cells, or physiological assessments, among other things. Drug develoPersonalized medicineent, illness detection, diagnosis, and therapy all benefit from the use of biomarkers. Proteomics makes use of a variety of methods, including mass spectroscopy, DNA, RNA, and stable isotope techniques, as well as metabolic, DNA, and RNA profiling. Metabolomics, or the study of molecules, is the investigation of quantitative variations in nonprotein small molecules associated to a biological or physiological situation. It is estimated that there are 5000 (between 1000 and 10) distinct small molecule metabolites in the human metabolome. In the realm of cardiovascular medicine, metabolite profiles for ischemia and CAhCA were vestigated [Chan IS et al., 2011].

Pharmacogenomics is the study of chromosomal abnormalities, DNA sequence alterations, and epigenetic modifications to chromatin and DNA (i.e., changes that do not impact DNA sequence). Pharmacogenetic methods aim to increase a medication's efficacy and safety by discovering the genetic components that affect interindividual variance in drug response. Pharmacogenomics is the study of how differences in a number of genes at the genetic (genome) level affect the diversity in drug response. Pharmacogenetics studies how variations in a single gene's genetic makeup impact the variety of medication responses (i.e., effectiveness and toxicity) [Kongkaew et al., 2014].

When a solid organ transplant, such as a heart transplant, is performed, the condition of the graft is monitored using peripheral blood mononuclear cell gene expression profiling.

3.3.1???????Cardiovascular Disease: Functional Aspect of Personalized medicine

As previously said, functional elements, such as imaging data, give a different perspective as structural aspects. The range of functional values in Personalized medicine must be established, nevertheless, and this is particularly difficult. Functional variables include things like heart rate variability, exercise testing, and endothelial function. In this section, the endothelium’s function will be emphasized. The endothelium secretes nitric oxide and other vasoactive chemicals to regulate vascular tone. NO mediates the endothelium’s protection by lowering vascular inflammation, vascular smooth muscle proliferation, platelet aggregation, and tissue factor production. The brachial artery’s flow-mediated dilation (FMD) allows for the assessment of endothelial function. Treatment for coronary heart disease includes lipid-modifying medications, blood pressure-lowering exercises, dietary changes, and cessation of smoking in order to repair endothelial dysfunction. It is necessary to standardize the FMD method and create new approaches to evaluate endothelial function in light of the contradictory study findings. Noninvasive peripheral artery tonometry, which analyzes endothelial dysfunction, is one of them and can forecast late CV events. The RH index, which measures reactive hyperemia (RH) response using peripheral artery tonometry, has been demonstrated to be associated with a number of conventional and metabolic risk factors. Moreover, the augmentation index (AI), a measure of arterial stiffness derived from PAT, demonstrated high reproducibility [Featino et al., 2016].

3.3.2 Challenges of Personalized medicine in Cardiovascular Disease

In essence, Personalized medicine is a multidisciplinary approach to science. Its widespread adoption will require the synchronization of a variety of factors, including technological advancements, changes to medical practice conventions and infrastructure, improvements to the effectiveness and quality of healthcare delivery, diagnostic and therapeutic business models for genetically designed markets, efforts by public and private players to justify a new category of tests and drugs, a new regulatory oversight strategy, and, of course, ethical considerations. A wide range of stakeholders who are all working toward the same goal of harnessing scientific and technical develop Personalized medicines to improve patient care are necessary for the develop Personalized medicine of Personalized medicine.

3.4 Personalized medicine for Parkinson’s Disease

Levodopa and other dopamine replacement treatments (DRT) continue to be the cornerstone of the treatment of PD. Although DRT and levodopa in particular have the ability to improve PD's motor symptoms, motor complications continue to plague the disease's therapeutic approaches. New difficulties have also emerged. As a multisystem, multi-neurotransmitter dysfunction-related heterogeneous condition, PD is now understood to exist. Therefore, we need to be aware of the "one size does not fit all" concept when it comes to treatment because in many cases, prescribing generic DRT may not be enough. Personalized medicine is based on taking into account patients' clinical phenotypes and particular personal demands before prescribing. According to the American Medical Association, customized medicine is "health care that is informed by each person's unique clinical, genetic, and environmental information." The concept of personalized medicine is ambiguous. For "single multifactorial" pathology-driven illnesses, personalized medicine is a crucial component to take into account and may need the use of "cocktail therapies." This idea is now especially pertinent to PD because of the many pathologies that have led to complicated motor and nonmotor illnesses.2 For instance, treatment for Parkinson's disease (PD) must consider a patient's lifestyle, genetic make-up, personality, pharmacogenetics, and sensitivity to adverse effects [Miedany, 2015]. The distinguishing enablers of this innovative, individualized treatment approach for Parkinson's disease are depicted in Figure 3.3. We acknowledge that some elements, such as genetics vs pharmacogenetics or aging with comorbidities, may have a significant amount of overlap. However, each of these factors must be taken into account separately for treatment to be truly personalized. Precision medicine based on genomics can be one of many sub-strategies under the umbrella of Personalized medicine. In this article, we look at a number of ideas that might aid in the creation of functionally successful tailored therapy for people with Parkinson's disease [Tezak et al., 2010].

3.4.1???????Advanced Treatment of Parkinson’s Disease through Personalized Medicine

In this study, researchers refer to DBS, LCIG, apomorphine injection, MRgFUS, and other non-pharmacological techniques as "advanced treatments".

Although the goal of advanced therapy for PD is to enhance motor characteristics, it has also been demonstrated that this treatment is successful for several non-motor aspects [Antonini et al., 2016]. Although speculated that the presence of off-symptoms for more than 2 hours per day, bothersome dyskinesia for more than 1 hour per day, and levodopa administration more than 5 times per day may be indicators for advanced PD, the timing of the introduction of advanced treatments like DBS or LCIG varies from patient to patient. The following are the authors' descriptions of PD patients' indications for advanced therapies. Good candidates for DBS, LCIG, and apomorphine subcutaneous infusion were patients with a good L-dopa response, excellent cognitive, and an age under 70. More precisely, DBS or LCIG can be used to treat individuals with bothersome dyskinesia. L-dopa-resistant tremor patients were thought to be ideal candidates for DBS. Based on each patient's background, motor and non-motor characteristics, and activities of daily life, previous authors also provide an indicator of whether device-aided therapy is appropriate by applying the Delphi technique. The criteria for individualized therapy may need to be further refined, though, when new choices become available. In addition, since it is presently unclear if these cutting-edge therapies are appropriate or inappropriate for certain individuals, we should be careful [Vogenberg et al., 2010].

DBS, LCIG, apomorphine, MRgFUS, cell therapy, and gene therapy are already available or may be available in the near future as advanced therapeutic options for PD motor characteristics (Figure 3.4). The major treatments for medication-resistant PD-related tremor are DBS, MRgFUS, radiofrequency, and gamma knife. In Supplementary Table 4.1, the features of each tremor therapy are displayed. The motor characteristics of PD are the main emphasis of the section below, which also briefly describes each pertinent advanced therapy. Table 1 lists briefly the indications, benefits, drawbacks, and side effects of the three currently available advanced therapies for PD: DBS, LCIG, and apomorphine [Sairamesh et al., 2013]

Patients are left with motor response variations and dyskinesias when oral dopaminergic medication fails to adequately treat Parkinson's disease, and these symptoms may have a significant influence on everyday functioning. One of the cutting-edge therapies that are now on the market, such as deep brain stimulation, continuous subcutaneous apomorphine infusion, and continuous levodopa-carbidopa intestinal gel, may be beneficial for them. The illness's progressive nature, the diversity of disease manifestation, and the range of patient characteristics will all be taken into consideration when discussing the indication, the decision between the many advanced therapies, and the timeframe.

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3.5 Microbiome at the Frontier of Personalized Medicine

With the develop Personalized medicine of next-generation sequencing, which has made it possible to characterize the gut microbiota in great detail using multi-omics approaches without having to culture individual microbes, which can be difficult in some cases, our understanding of the function of the microbiome underwent a revolutionary change. The 16S ribosomal RNA gene, which is highly conserved in bacteria with low environmental variation, is used as a marker gene in the most common way to define microbial communities.

3.5.1 Microbiome as a Tool for Precision Diagnosis and Personalized Treatment Strategies

In addition to the well-documented connections of changes in microbial community structure in various disease states, the gut microbiome is playing an increasingly important role as a biomarker for disease phenotype, prognosis, and responsiveness to therapy. One of the well-studied dysbiosis-related illnesses is inflammatory bowel disease, with the microbiome acting as a key indicator of disease phenotype and therapeutic response. There are three main types of inflammatory bowel disease [Hammerstrom et al., 2011].

3.5.2 Microbiome as a Determinant of Human Therapeutics

Like in every ecosystem, the ecology of a microbial community depends heavily on interactions between various species. It is not unexpected that bacteria have developed gene cassettes for using chemical weapons because their survival and develop Personalized medicine are heavily influenced by their chemical environment. In fact, antibiotics were originally discovered in microbial culture as a distinctive trait of colonies, and since then, more extensive analyses of the soil microbiota have found an even wider variety of antibiotics [Hammerstrom et al., 2011].

3.5.3 Targeting the Microbiome to Improve Health

The allure of the microbiome lies in its flexibility and human capacity to alter its constituent parts, in addition to acting as diagnostic and therapeutic biomarkers and modifying therapeutic responses to medications by maintain proper 5S (Figure: 3.5). Antibiotics have traditionally been used to target microbial populations because they are both necessary and efficient for treating systemic infections that are often brought on by pathogen invasion. But the unforeseen side consequences on microbial [Hammerstrom et al., 2011].

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4.????Factors Related to Personalized medicine

4.1 Condition-related factors

Polypharmacy, having comorbid diseases, and having mental disorders including depression were condition-related variables linked to worse drug adherence. However, having a history of screening as well as having a history of falls were linked to higher drug adherence which is shown in figure 4.1.

4.2 Patients related factors

Demographics, physical and mental health, illness and treatment, family history, and menopausal variables made up the six key characteristics linked to patients. Poorer drug adherence was associated with lower education levels. Greater menopausal age was also associated with worse drug adherence.?Misperceptions concerning osteoporosis and the absence of perceived benefits of therapy were among the diseases and treatments that people perceived [Latimer et al., 2018].

Patients will start acting more like customers, driving demand, as they become more aware of the advantages of customized care, including the power of genome sequencing. Patients would greatly prefer data-driven, tailored care delivery than in the past, when choices were frequently based on instinct, intuition, and the expertise of certain doctors.

In addition, patients will want access to personal data and crucial health indicators as well as a greater level of active participation in shared decision-making. For instance, Roche Diagnostics' Accu-ChekView package enables diabetics to regain control over their condition and stop type-2 diabetes from developing by assisting them in making lifestyle changes.

The knowledge and awareness of one's own health are both increased through gamification goods like wearable fitness trackers and apps like the Accu-ChekView package. Even if a provider has access to genome sequencing, the greatest diagnostics, and individualized therapies, the effectiveness of care is heavily dependent on a patient's capacity to alter their behavior after leaving the doctor's office. For this reason, change management agents are essential [Kulkami et al., 2014].

A doctor has no influence over a patient's capacity to fill a prescription or on personal behaviors like smoking, exercising, or eating well.

Health monitors, gamification, and education are essential tools for empowering people to take charge of their own health.

4.3 Health system-based factor

Care provided by various medical specializations and a dearth of patient education were health system-based variables linked to worse drug adherence. Another contributing issue was a lack of easy access to medicines [Kulkami et al., 2014].

4.4 Socioeconomic related factor

Residence location and current smoking status were socioeconomically relevant variables. Additionally, expensive medical care had an impact on drug compliance. When prescribing antiosteoporotic drugs that are more expensive than others, doctors should consider their patients' financial situation and, if required, send them to social services [Kulkami et al., 2014].

4.5 Therapy-related factors

Higher dosage frequency and pharmaceutical adverse effects were therapy-related variables.?According to the study, clinicians should remember these things these factors in mind to ensure that their patients stick to their prescription regimens [Kulkami et al., 2014].

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Figure 4.1: Factors of Personalized medicine

4.6 Drug Develop Personalized medicine Related Factor

There are several drugs develop Personalized medicine factors:

·????????Optimize its ability to target the intended site

·????????Remain attached to the site

·????????Optimize its strength (Potency, efficacy, effectiveness)

·????????Optimize safety.

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4.7 Gene Related Factor

According to Ho et al. (2010), drug and alcohol dependency is a complex psychiatric illness that arises from a confluence of environmental, genetic, and drug-induced risk factors. Family, adoption, and twin studies, which show significant heritability with an estimated 50% [Uhl et al., 2008], strongly support the genetic foundation of reliance. The data points to the fact that while several gene changes each make a tiny contribution to this risk, no one variation appears to account for a significant fraction of it [Shijet et al,. 2016].

Pharmacogenetics is the study of the genetic aspects of medication toxicity and response. We briefly outline the fundamentals of pharmacogenetics in this review before giving examples of recent findings that show how genetic diversity affects drug dependency, drug effects, and drug-induced behaviors. Understanding the processes behind the variance in the risk for dependency is the main objective of pharmacogenetic research into drug misuse. There are some genotypes that are associated with a greater risk of drug dependency, and several of the research we examine have discovered these genotypes. We also emphasize how pharmacogenetics, by exposing genetic differences that foretell individual reactions to therapeutic interventions, might improve the creation of tailored medicines [Denisenleo et al., 2018]

4.7.1???????Principles of Pharmacogenetics

The emphasis of pharmacogenetics is variation in the human genome. There are around 30,000 genes in the human genome, and each one is made up of a sequence of hundreds to thousands of nucleotides (DNA units; Figure 4.2). Most genes are inherited twice per individual, one from each parent. Despite the fact that the DNA of any two people is nearly 99 percent identical, the human population nonetheless contains millions of variant sequences due to the 3 billion nucleotides that make up DNA [Kruglyak and Nickerson., 2001]. Polymorphisms are variations that occur in more than 1% of the population. The single nucleotide polymorphism (SNP, pronounced "snip") is the most prevalent kind of variation; insertions, deletions, and tandem repeats are additional frequent types (Figure 4.3).

Figure 4.2: DNA Unites.

A molecular product, often a protein, is encoded (provided a template for) by each gene's nucleotide sequence. Changes in the gene's product due to sequence variation may modify the phenotypes (traits or characteristics, such as a disease or treatment response) that the product impacts.

To identify and investigate the links between genes and phenotypes, genetic researchers employ a variety of methods. The proportional contributions of genetic and nongenetic (environmental, for example) factors to a specific trait can be determined using heritability studies. Linkage studies focus on sections of the genome that may contain genes linked to interesting characteristics by analyzing the pedigrees of related individuals and genetic markers. Linkage studies have shown a relationship between genes and phenotypes. Candidate gene association studies may be used to explore this relationship as well as to concentrate on specific genes chosen for their physiological or pharmacologic significance to a phenotype. Genome-wide association (GWA) studies compare hundreds of thousands of gene variations in DNA samples obtained from a large number of individuals in an effort to identify connections between genes and phenotypes[Shijet et al,. 2016].

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Figure 4.3: mRNA Transcription

Pharmacogenetics has traditionally concentrated on the impact of genetic variation in pharmacodynamics (e.g., drug-response proteins, such as receptors, channels, and transporters) and pharmacokinetics (e.g., the absorption, distribution, metabolism, and excretion of medicines) (Figure 4.4). However, other genetic impacts on drug misuse and dependency have been discovered through candidate gene research and, more recently, GWA investigations. GWA investigations are potentially good tools for finding novel common genetic variations and new genetic biomarkers that link with certain phenotypes since they cast a wide net and lack a hypothesis about which genes are involved. For instance, GWA studies have demonstrated that genes involved in a variety of processes and functions, including transcriptional control, enzymatic activity, cell adhesion, and many other processes and functions, may be linked to dependency symptoms.

Figure 4.4: Neurotransmitter Transformation

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4.8 Economic Related Factor

A lot of the debate and controversy surrounding pricing and competition in the pharmaceutical industry is caused by the fact that patent protection permits businesses to charge exorbitant rates for potentially life-saving therapies. Without patents, additional businesses would be drawn into the market by the substantial profits made by leading companies. By lowering costs and boosting access to important treatments, such entrance would probably improve current-period wellbeing.

However, society enacts laws that forbid this entrance in the pharmaceutical industry and other businesses that rely on intellectual property, permitting huge price-cost margins to remain for a while. In order to provide businesses the right incentives to undertake significant fixed-cost investments in new items, policymakers tolerate the lower production caused by increased pricing. In order to provide strong incentives for future innovation, there is an implicit trade-off where some present welfare is lost.

The capacity of companies to develop treatments for limited, focused patient groups has changed, according to one line of inquiry. These goods are frequently accompanied with diagnostic tests that can predict a product's potential effectiveness in a particular patient. In general, these medications fall within the expanding umbrella of precision medicine. More than just a scientific develop personalized medicine or a curiosity, businesses' capacity to create these items is significant. When the boundaries of our current intellectual property system were being formed, the pharmaceutical industry had quite different economic underpinnings than one that involves goods aimed at tiny patient groups today.

In a clinical study, biomarkers can be used for a number of different things. These goals could all—but not all—have anything to do with precision medicine. For instance, a biomarker that measures a product's toxicity across the board can be used; while useful, it isn't particularly pertinent to targeting. We are mainly interested in studies that use biomarkers to identify patient categories who are more (or less) likely to respond to specific treatments when analyzing the economic develop Personalized medicine in the pharmaceutical industry. In order to identify those associated with products that we classify as "likely precision medicines" (Personalized medicines), we thus need additional information on the function of the biomarker in a study. Figure 4.5 illustrates the evolution of these Personalized medicines studies through time and demonstrates a rise in their application throughout all clinical development Personalized medicine phases. Phase I studies for Personalized medicines, in particular, have increased significantly in recent years [Shijet et al., 2016].

Figure 4.5: Personal Medicine Development Trial Report

4.9 Drug Regulatory and Policy Maker Related Factor

A regulatory agency is a governmental body or government organization tasked with exerting independent control over a particular domain of human activity in a supervisory or regulatory role.?An independent regulatory body is a regulatory body that is apart from other governmental branches or arms.

Administrative law regulation or rulemaking is a topic that regulatory agencies deal with. The necessity for quick application of public authority in some areas, the intricacy of some regulatory and supervisory activities that call for competence, and the negative effects of political meddling all serve to justify the creation of independent regulatory bodies. Independent regulatory organizations may conduct audits or investigations, and some may have the power to impose fines and impose restrictions on the parties involved.

Regulatory agencies often fall within the purview of the executive department of government, or they are given legal permission to carry out their duties under the control of the legislative branch. Their acts are typically subject to judicial scrutiny. Regulatory agencies are frequently established to uphold safety and standards, monitor the usage of public goods, and control trade.

Some International Drug Regulatory Authorities are: ?

·????????International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) ?

·????????European Medicines Agency (EMEA) ?

·????????Therapeutic Goods Administration (Australia) (TGA) ?

·????????U.S. Food and Drug Administration (FDA) ?

·????????Medicines and Healthcare Products Regulatory Agency (MHRA)

The drug system consists of four major stages, including research and develop Personalized medicine, regulatory review, medication manufacturing, distribution, and marketing, and medication use. Each stage has a number of crucial control points where issues with quality, safety, and efficacy can be addressed and breakdowns can happen. This chapter gives a general review of the key elements of the pharmacological system, areas that might directly or indirectly result in mistakes, and chances for growth, healing, and progress.

Currently, there are more than 10,000 prescription medications and biologics on the market in the United States (FDA, 1999), and there are more than 300,000 over-the-counter (OTC) items as well (RSW, 2001). Because of production and distribution issues or severe adverse effects, 215 prescription pharmaceuticals and 71 over-the-counter medications were recalled in 2004 (FDA, 2004a).

Over the past century, the regulatory aspect of the drug system has changed from being primarily concerned with interstate transportation and misbranded products to being built on an infrastructure with the aim of dependable standards, processes, and laws to at least partially guarantee the safety and efficacy of therapeutic agents. As a consequence, a complex, thorough pharmacological system with four phases that interact, support, and reinforce one another to varied degrees is created (Figure 4.6):

(1) Research and develop personalized medicine (R&D), where concepts for new drugs are developed and candidates are clinically tested;

(2) Regulatory review by the Food and Drug Administration (FDA), to validate or refute the research findings and ensure accurate labeling;

(3) Manufacture, distribution, and marketing of products that have received regulatory approval; and

(4) Use of drugs available either through a prescription or over-the-counter (OTC).

This paradigm is used for biologics, prescription medications, and some over-the-counter products. For other OTCs and generics, the steps of product develop personalized medicine and regulatory approval are condensed.

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Figure 4.6: Steps of New Drug Approval

List of Essential Drugs: The Government establishes Maximum Retail Prices (MRP) for 117 essential pharmacological chemical compounds in accordance with the pharmacological (Control) Ordinance 1982. Only local producer firms are included in this pricing decision, while global corporations are still using their own methods to set prices for their products.

The growth of this industry has been greatly aided by the Bangladesh Association of Pharmaceutical Industries, or BAPI (Bangladesh Aushad Shilpa Samity in Bengali), which was founded in 1972 with just 33 members. At now, BAPI is a highly powerful association with 144 corporations as members [DGDA., 2023].

Major Function of DGDA

1. Evaluation of the proposals of new projects of all systems of medicines.

2. Issue and renewal of drug manufacturing licenses.

3. Issue and renewal of retail and wholesale drug licenses.

4. Registration and renewal of drug products.

5. Fixation of price and certification of price for drug products.

6. Inspection of pharmaceutical establishments

7. Approval of block list for the import of raw- and packaging materials.

8. Approval of indent for import of finished drugs.

9. Surveillance and pharmacovigilance activity

10. Prosecution of cases in the drug courts and other courts

11. Issue of export licenses, FSC (Free Sales Certificate), GMP (Good Manufacturing Practices) Certificate & CPP (Certificate for Pharmaceutical Products.)

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5.????Personalized Medicine in Bangladesh

As previously said, many hospitals in Bangladesh are starting their journey in personalized medicine especially in the oncology department. One of the most advanced high-tech industries in Bangladesh's economy is the pharmaceutical sector. Only 173 of the 210 licensed allopathic drug-making facilities in the nation were actively producing medications in 2000; the remainder were either shut down on their own or suspended by the licensing authority for drugs as a result of breaking drug laws or good manufacturing standards. Currently, there are roughly 300 pharmaceutical businesses in operation. In various dosage forms, the sector produced around 5,600 distinct brands of pharmaceuticals. However, Bangladesh has around 37,700 retail drug license holders and 1,495 wholesale drug license holders.

The growth of this industry was hastened when the Drug Control Ordinance of 1982 was published. The primary driving forces behind this progress are the professional expertise, ideas, and inventiveness of the pharmaceutical specialists working in this field. The industry is exporting medications to international markets, especially the European market, as a result of recent progress in this area. Additionally, this industry meets 97% of the local market's whole need for medicines. A few of the businesses manufacture products like insulin, hormones, and anticancer medications that were not previously made in Bangladesh. Leading pharmaceutical firms are growing their operations with the intention of entering the export market. To increase the strength of this sector, a few new industries with high-tech machinery and workers have recently been founded.

The pharmaceutical industry in Bangladesh mostly sells branded generics. Bangladeshi pharmaceutical companies have three options for customers: the public health care system, the government, and foreign agencies working in Bangladesh (like UNICEF). The local pharmaceutical business in Bangladesh is mostly controlled by producers there. Local businesses in Bangladesh hold a market share of up to 97% of the country's overall pharmaceutical market, while MNCs have a meager proportion. All but one of the top 10 pharmaceutical firms in Bangladesh are homegrown firms. The two leading local producers, Square and Incepta pharma, together account for more than 30% of the nation's whole pharmaceutical industry.

Since its founding in 1972, the Bangladesh Association of Pharmaceutical Industries (BAPI) has played a crucial role in the development of personalized medicine of the sector. Large, medium, small, national, and international businesses that make up the association's membership collectively produce 97% of the nation's pharmaceutical output.

The same active ingredients as the original formulation and bioequivalence to the brand-name counterpart in terms of pharmacokinetic and pharmacodynamic properties (equivalent absorption rates, elimination rates, and other in vivo effects) are considered to be signs of quality for generic pharmaceutical products. Generics are hence expected to be the same as the original product in terms of dosage, strength, administration method, safety, effectiveness, and intended purpose.

While some of the pharmaceuticals available in Bangladesh meet international standards, some don't. Interviewees from the medical and pharmacy fields offered passionate comments on the relative quality of various brands. Although more thorough and systematic investigation is needed to evaluate Bangladesh's pharmaceutical quality, there have been some anecdotal allegations of inferior-grade medications.

A regulatory agency is a governmental body or government organization tasked with exerting independent control over a particular domain of human activity in a supervisory or regulatory role.

An independent regulatory body is a regulatory body that is apart from other governmental branches or arms. The Directorate General of Drug Administration (DGDA) and The Pharmacy Council of Bangladesh (PCB), two governmental and semi-governmental institutions, respectively, control pharmaceuticals and pharmacies in Bangladesh.

The DGDA: The Directorate General of Drug Administration Bangladesh's DGDA, which is a division of the Ministry of Health and Family Welfare, is the country's drug-regulating body. All operations including the import and export of raw materials, packaging materials, manufacture, pricing, licensing, registration, etc. of all types of medication, including those of Ayurvedic, Unani, herbal, and homeopathic systems, are governed by DGDA.

To regulate pharmacy practice in Bangladesh, the Pharmacy Council of Bangladesh (PCB) was founded in 1976 as part of the Pharmacy Ordinance.

The International Pharmaceutical Federation and the Commonwealth Pharmaceutical Association are both connected with the Bangladesh Pharmaceutical Society. The WHO's current Good production Practices (GMP) shall be carefully adhered to, and production facilities will undergo routine DDA inspections, according to the National Drug Policy of 2005. Other important aspects of regulation include limitations on imported medications, a prohibition on the manufacture in Bangladesh of around 1,700 medications deemed unnecessary or hazardous, and severe pricing regulations that apply to 117 major medications [DGDA, 2023].

5.1 Drawbacks of Personalized medicine

5.1.1 API Industries in Bangladesh

Bangladesh’s pharma market is an import base market. There are no API industries in our country. But for Personalized medicine, it is very important to build an API industry to supply an adequate amount of medicine to the patients.

Pharmaceutical businesses are steadily improving their ability to generate the raw ingredients required to build medications, which will help Bangladesh become less dependent on imports and strengthen its position as a worldwide competitor. Thanks to the arrival of additional companies into the market in recent years, the value of active pharmaceutical ingredients (APIs) produced in the nation increased four times over the previous 12 years to above Tk 2,000 crore. In 2010, it was around Tk 500 crore.

According to Abdul Muktadir, chairman and managing director of Incepta Pharmaceuticals, "The pharmaceuticals sector will not face severe challenges after Bangladesh is graduated from the group of the least-developed countries in 2026 because we are building our capacity of making APIs." The number of companies producing APIs has increased from 10 to 15, according to SM Shafiuzzaman, secretary-general of the Bangladesh Association of Pharmaceutical Industries, which represents 265 local pharma manufacturers which is shown in figure 5.1 and includes Eskayef, Square, Beacon, and Beximco.

Figure 5.1: Reports of API Park in Bangladesh

5.2 Mechanical Support for Personalized medicine?

In the pharmaceutical industry, all companies are using their importer large machine, which produces huge amounts of medicine at a time. But in the case of Personalized medicine, a small amount of medicine is needed which is difficult for companies with high financial costs.

5.3 Collaboration

It is essential to work closely with general practitioners, provide the public with more information and support, and foster communication between hospital-based physicians and general practitioners. The first people who can persuade patients to try personalized medicine are general practitioners. Cooperation between patient advocates (who require personalized medicine), researchers, and doctors as well as improved collaboration between scientists and physicians and industry, governments, and international organizations, is also crucial. A direct connection between general practitioners and research hospitals is also necessary [Quinn et al., 2016].

It is crucial for regulatory agencies and healthcare management to work together to raise both parties' knowledge of the issue and develop coordinated intervention strategies.

5.4 Data Protection

Better and publicly verifiable protection of personalized medicine data is essential to ensuring that patients are comfortable sharing it for their personal needs as well as for inclusion in aggregated data sets used to create personalized medicine methods for other people.

Access restrictions to patient/citizen data should be eliminated as well. Building data-sharing infrastructure is therefore necessary, as the use of technology to support clinical decisions can put vast amounts of data in the hands of doctors, facilitating their decision-making and allowing them to choose the best course of action for that specific patient.

To ensure that data is widely available, pharmaceutical firms should pledge to provide data from all trials and clinical studies [Jin et al., 2019].

5.5 Education

Education and discussion on the concept of personal health are essential, both for a big forum of politicians and for the general public. Industry, governments, institutions, organizations, and patient advocates should work together and educate one another.

Additionally, it is crucial to educate the public about the advantages of personalized medicine Therefore, it is essential to make investments in patient literacy, involvement, engagement, and empowerment as well as to make modifications to university curricula and the professional (doctors, nurses, and others) lifelong learning program.

More training must be organized, and GPs, patients, healthcare providers, and payers all need to be made more aware, among others. It is crucial to better inform patients about the advantages of personalized medicine [Bolha et al., 2017].

5.6 Finances

Personalized medicine calls for significant investment. Hard choices concerning the economic implications for other treatments and the accessibility of hyper-personalized care may need to be made. To enable this, better, more frequently updated guidelines and data-driven, evidence-based decision support algorithms are required.

The healthcare system has to be geared toward value-based healthcare, the industry needs to enhance the cost-benefit ratio, and sickness funds and health insurance need to be controlled such that they are concerned with long-term health and cost reduction (and not simply with short-term savings).

Additionally, there ought to be increased investment in interoperability and the digitization of health data. It's crucial to alter governance while providing the right financial incentives. It is important to build sustainable lighthouse programs and financing/frameworks for continuing successful projects (which are frequently stopped after the original funding term). The "one-size-fits-all" theory and insurance are the foundations of healthcare economics. The whole health system will be affected by changing the economy through personalized medicine. Additionally, the public health system should pay for telemedicine/ personalized medicine services, and there has to be a designated budget for investing in personalized medicine solutions [Sanchezet et al., 2019].

5.7 Public

Residents of it might be the catalyst for change. They must be informed of the benefits of personalized medicine, and they must participate in and influence decision-making. In order to discover the best solutions, it is also important to understand the issues that patients and healthcare professionals confront locally. A citizen needs illustrations. It is essential to provide patients the freedom to request—or even demand—the transition to a better paradigm.

The most essential thing to remember is that patience is needed, along with ongoing efforts to bring stakeholders from many fields together and simple adoption techniques that support the gradual, step-by-step implementation of new ideas.

5.8 System Changes From Governmental Level

A system reform is essential for improved personalized medicine information distribution. If personalized medicine is implemented on a wide scale, which would need a lot of work on many levels, it will be necessary. The worst error is to hope for quick, broad victories.

Guidelines for implementation and payment should be created on a national and international level. Establishing political support for a healthcare system that prioritizes personalized medicine is necessary, and significant personalized medicine integration necessitates many paradigm shifts in both the public option and decision-making.

The healthcare system should be reformed as well, according to respondents, along with the systemic approach and interaction with public actors and HTA agencies and the need to improve governance via the use of suitable financial incentives.

Additionally, vested interests' impact on how specific medications are prioritized must be eliminated [Jiang et al., 2018].

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6.????Conclusion

Personalized medicine may be able to meet the need for better health outcomes by cutting back on time, money, and healthcare expenses associated with medication develop personalized medicine. This shift in the healthcare system will only be possible with the equal participation of patients and consumers in clinical trials, the develop personalized medicine of smart tools and the analysis of genetic data by innovators and entrepreneurs, education of consumers and providers by regulators, understanding of diseases at the molecular level by doctors, and support from academic researchers who will work alongside innovative research projects. The impact of personalized medicine on the healthcare system may be advantageous. In the future, each person will obtain their whole genetic information on the day of their birth to be entered into a unique medical record using the tailored method. Based on patient exposure to various diseases, this information would enable doctors and clinicians to execute more efficient healthcare measures.

In Bangladesh Personalized medicine is very useful because it makes it easier to determine which course of action is best for a certain patient and it aids in the prevention, detection, and treatment of a number of disorders. On the other hand, it is a very time-consuming method. If the government should take the necessary steps for established personalized medicine in government hospitals and educate their doctor about personalized medicine. It would be very beneficial for the patients. Personalized medicine will play a very important role in the journey of Digital Bangladesh. So all the pharmacists and doctors are hoping that the Bangladesh government should take the necessary steps to establish personalized medicine in our all hospitals.

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