New Drug Approved For Tuberculosis: Golden Gem for XDR and MDR TB

 According to notice published on its official website, FDA has approved a new drug named pretomanid tablet in combination with bedaquiline and linezolid  for the treatment of extensively drugs resistant tuberculosis of lungs. FDA principle deputy commissioner Amy Abernethy, M.D., Ph.D stated that threat of antimicrobial-resistant infection is key challenge faced as a public health agency. This new treatment is claimed to be highly Potent than any other treatment options available till date

Key features of New Regimen

#   This combination contains a new drug Pretomanid which is  combined with bedaquiline (Approved in 2012 as combination therapy for multidrug resistant bacterial TB/MDR-TB) and linezolid (already marketed drug for treatment of multidrug resistant including streptococcus and methicillin resistant staphylococcus aureus) in  tablet form. 

# This combination is for limited adult patient with extensively drug resistant treatment intolerant or nonresponsive multidrug resistant

# Before approval, clinical trial was conducted in 109 patients with extensive drug resistant, treatment intolerance and non-responsive multi drug resistant TB of lung. All the efficacy and safety data were assessed and found to be satisfactory according to regulatory requirements with typical success rate of 95 %. (whereas the previously available treatment has only 34% in XDR and 55 % in MDR TB)  

#    Duration of treatment for this new drug combination is total of 6 months, much shorter than the available one (18 -24 months).

# Adverse drugs reaction profile is also considerable weighing risk-benefit ratio. Demonstrated reactions were peripheral neuropathy, hyperamylasaemia, mild hepatic enzyme elevation, hypoglycaemia, anaemia and general gastrointestinal upset.

Approval was taken from a special regulatory guidance under FDA called ‘limited population pathway for antibacterial and antifungal drugs’ by providing priority review and orphan drug designation which provides special incentives to encourage the development of drugs for rare disease.

Why new drug is appreciable over existing one?

According to WHO, in spite of availability of treatment and aggressive TB eradication programmes worldwide, by the end of 2016, the estimated number of  new cases of MDR TB was 4,90,000 from 123 WHO member states countries and the reliable data suggested about 6.2% of those are XDR-TB. The real scenario might be more intimidating than data suggested, because most of countries with low-socioeconomic status do not have proper detection facility.

This new treatment will be more fortunate for the countries like India which accounts for more than 9,000 XDR TB cases, second highest after Russia throughout the world.

Long duration of treatment and high side effect profile is One big reason of failure of previously available treatment. Behind Mere success rate of bedaquiline treatment, Patient withdrawal was the major reason. Practitioners stated, “retention of patient throughout the duration is more challenging than anything else.”

Behind high patient withdrawal rate, excessive side effect profile is major contributing factors. As of now, the available evidences suggest that this new treatment is going to fill this gap. 

What actually XDR and MDR TB means?

When two most powerful anti-TB drugs isoniazid and Rifampicin are resistant during treatment, that is referred as MDR TB and along with these two drugs if resistance to any of fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin etc.) and at least one of three injectable second line anti tubercular drugs (amikacin, capreomycin and kanamycin), such condition is referred as extensively drug resistance  (XDR-TB).  Both MDR and XDR TB takes longer duration of treatment than drug susceptive TB with low success rate and high mortality.

Sources of development of such TB is mainly because of improper treatment of susceptible TB. Condition might have resulted from faulty prescription or improper regimen of prescribed treatment. On other side people with MDR and XDR TB can transmit the resistant disease pathogen.

Total of 19 XDR Tb cases were reported in Nepal in 2017; number is much higher for MDR. This available new treatment may be an golden opportunity to “stop TB in Our lifetime”. 

                                                        Thank You !!!

References: 

1. https://www.who.int/tb/areas-of-work/drug-resistant-tb/xdr-tb-faq/en/ 
2. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-resistant-forms-tuberculosis-affects-lungs
3. https://www.ghdonline.org/ic/discussion/issues-and-threats-of-tuberculosis-in-nepal/
4. http://tbonline.info/posts/2018/5/5/managing-mdr-tuberculosis-nepal/
5. https://www.ncbi.nlm.nih.gov/books/NBK138752/
6. https://www.who.int/tb/areas-of-work/drug-resistant-tb/xdr-tb-faq/en/

Qualitative Research, Understanding of Focus Group Discussion and Personal Interview

There is the practice of occult spiritualism for treatment of various ailments in tribal community of Nepal, specially in rural area. Such practices are not only limited in rural places but outreached to urban area also. They have their own treatment methods, defined centres, practitioners and people following them regularly. Let’s say researchers are interested to know the factors behind its existence and peoples belief toward these practice even at the time of scientifically stablished conventional treatment system. What methodologies will researcher follow? How data will be collected? what should be the purpose of study? 

                     Exploratory research

As in above-mentioned real-life scenario, the prime purpose of researcher is to know something about this unknown and unexplored practice. Such studies are termed as exploratory research, where we search for new concepts, idea, belief, attitude, and impact on society etc. which has not been explored before. For the future research, the collected data and conclusion of study, will be the foundation for descriptive research, which will dig deep with defined questioner, sample size, statistical methods to get more concrete information over the facts established by exploratory research. Exploratory research always probes to gets answer of ‘what’ and ‘why’ and methodology followed is obviously qualitative research method.

               Qualitative research method

This is method of enquiry, that helps in-depth understanding of problems or issues or our matter of interest in their natural setting by non-statistical methods. The whole research process is dependent upon experience of investigator with the participants regarding that particular research question. Different methods are being employed to collect data such as focus group discussion, in depth interviews, ethnographic research, text analysis and case study research. Here, former two methods -the most commonly used will be discussed

                              In depth interviews

v Patients are enrolled from one particular treatment centre who

are participating already in our concerned subject matter 

v Questioners mainly asked why they are using this particular treatment

vSemi-structured questioner is used with intent of getting information on disease, psychology, socioeconomic and other confounding factors

v Before reaching to patients/participants, consent has to be taken from those hospital/healer/practitioners to use their patient after explaining the objectives of the study

v Inclusion/exclusion criteria is varied according to objectives. Generally, for in depth interview, investigator as well as participants should know the vernacular language.

v Number of Participants recruited be determined by the information they are providing. Unless there is no new information given by the participants, recruitment continues.

v Interviews are conducted in private room, where participants feel comfortable to share their personal belief, experiences and any confidential information.

v Generally, one investigator conducts the interviews and 1or 2 assistant will help by collecting data. 

                       Focus group discussion

v Conducted to know the general view of community toward that particular treatment or researcher problems.

v Generally peoples who are well known about the topics are gathered together in different groups and a moderator will facilitate the discussion within the group members.

v Again, semi-structured questioner is employed to know peoples view and every idea are appreciated. Experience of moderator will play vital role to get more interesting facts by throwing probing questions.

v Number of groups can be variable according to demographic distribution of community. 

   Different approach of data analysis 

The collected information need to be organized and analysed in qualitative study also but different approach is employed. There is no any predefined data analysis methods. Here nature and extent of information collected during FGD and personal interview will determine what approach will be appropriate for data analysis. These are the basic steps of data analysis in qualitative research. 

v Transcribing all data: converting the data into textual format.
v  Organizing data: a tedious process which demand great effort.   Finally clean data will be obtained according to research objectives
v Coding: expression of data into understandable format for software. 
v  Data validation: accuracy and reliability of data is validated throughout the process. 

v Conclusion of data: Finding the research outcome according to objectives. 

Applicability of Qualitative research 

v In general, this method is extensively applied in Market research related to consumer satisfaction and impact of the product on market demand.

v In epidemiology, impact of any treatment, health care service, new health governance and its impact on social structure, traditional belief in community etc. can be studied.

v In clinical research scenario, qualitative methods helps in advancement of healthcare system. Eg: novel monitoring of COPD via mobile-health technology.

v  In psychology, qualitative research has been extensively used to know human social behaviour and cultures. Social phenomenon like experiences, perception, behaviour and aspect related to it can best understood in natural setting rather than experimental.

v Library and information system (LIS) can use this method to expand their horizon. 

                                                 Thank You !!!

    

   References For Further Reading 

1. https://www.questionpro.com/blog/what-is-research/
2. https://www.cambridge.org/core/journals/the-psychiatrist/article/qualitative-research-its-value-and-applicability/51B8A4C008278BA4BA8F518060ED643C
3. https://keydifferences.com/difference-between-exploratory-and-descriptive-research.html 
4. https://www.youtube.com/watch?v=FlBFdEgrTBM

How To Find Appropriate Literatue In PubMed

               Basic steps of literature search  

1.     Learning the steps of literature search process

2.     Understanding MeSH

3.     Determining the database searching techniques

4.     Conducting an advance search in PubMed

5.     Accessing the literature

     Essential terminologies for literature searches

ü Keyword: These are the words or phrases that researcher types in search engine/database. Keywords defines the questions/concepts we are searching about, and results are displayed accordingly. Narrower (specific) the keyword is, higher the chance of getting appropriate results. 

üMeSH (Medical subjects headings) is the national library of medicine-controlled vocabulary thesaurus, used for indexing articles for the MEDLINE/PubMed databases. Each article citation is associated with a set of MeSH terms that describes contents of citation. MeSH terms are organized in a tree with sixteen main branches such as anatomy, organisms, disease, publication characteristics and so on. Searching with MeSH is preferred over keyword searching.

           Stepwise methods of searching literature

1.     Break down the search topic into different steps:

ü Depending on types of data we are searching, keywords are also constructed accordingly.

ü Generally our search topics for experimental study results contain intervention, diagnosis and outcome keywords.

Eg: chemotherapeutic agents for breast carcinoma. Here four major keywords are used (chemotherapy, agents, breast and carcinoma)  

2.     Gathering keywords

üFor gathering keywords, Google, Google scholar and Wikipedia are used

ü Google search shows thousands of results for any keywords, including journals, official and personal websites, blogs and patient information sites. most of information by random searching are of no use. Results can be limited by directing googles algorithms to particular types of sources like site.gov, site.edu, site.org at the end of keyword.  Generally limiting .gov is preferred one to get more relevant results (governmental agencies provides data on .gov. country shortcut)

Here,  keyword 'peptic ulcer' is typed by applying two methods- random searching and specifying the algorithms. Former search showed large number of sites designed to provide  general information and later displayed only governmental sites with authentic results. 

ü Wikipedia is preferred to get background information, and references & external websites. But, content itself is not preferred in scientific communities.

ü Google scholar provides scholarly information like books, Journals articles and patents. One special characteristic of google scholars is it shows results in order that higher the article is sited for, higher will be the rank-older articles are prone to be ranked high.  

3.     Search the concepts separately in PubMed

ü Once we done with gathering keywords, we now search that particular keyword in PubMed search box.

ü Relevant MeSH terms (medical subjects headings) are searched. It’s the set of controlled vocabulary terms used by national library of medicines. In pubmed, articles are assigned in subject specialists who read over the article and determines the subjects contents. Applying MeSH term ensures that articles in same subjects are grouped together regardless of the vocabulary used by author. MeSH descriptors are arranged in a tree structure that allows to search the different level of specificity 

 Here, firstly the search icon was changed to MeSH, then keyword is typed, total of 15 major MeSH were displayed, Each  heading again contains subheadings arranged in a typical tree format. 

4.  Apply additional Database search techniques

   

I.  Truncation

ü Addition of symbol using an asterisk at the end of word stem to find variant of root word and this is very useful to find synonyms. Eg: incubat* (incubator, incubation, incubating, incubated, incubates)

II  Quotation Marks keep terms together and in order. Eg: cervical cancer metastasis contains three keywords which can be represented as one by “cervical cancer metastasis”.

III.Parentheses: allows users to combine the concepts. They are used in the same manner that are being used in mathematics equation and allows ordering the set of terms. Eg oesophageal carcinoma (adenocarcinoma).

IV.  Boolean operators

ü They are used to narrow the search and helps to find the relationship between the search terms when searching in electronic databases.

ü Three Boolean operators are AND, OR and NOT.

ü AND narrows the search by combining together two separate topics. Putting treatment And outcome Helps to find the article which contains both these concepts. Eg: child* AND “head injury”. Quotation marks is used to keep two words as a phrase and * to find the variants on this word.

ü Using OR Boolean operators broaden the search and this is often used with synonyms child* OR paediatrics OR infants* OR adolescence*.

ü Using NOT will narrow the search. It helps to remove the terms we want to exclude. Eg: childhood diarrhoea NOT rotavirus.

here, I searched for Tamsulosin and 'benign prostatic hyperplasia', by applying AND & OR. former showed 838 results where both the terms are being used, and later showed 14359 results where either of these two terms are used. 

use of NOT is dependent on knowledge & understanding of researcher.

5. Apply filter:

Filtering article according to our wish is available in pubmed, on the left hand side of the result. Applying filter reduces the number of articles significantly and increases the accuracy. 

also, literatures can be filtered by author name. After entering keyword/MeSH, authors short name in this bracket […] will show exact literature you are searching for..

                                                                    Thank You !!!

References: 

1. https://www.nlm.nih.gov/bsd/disted/meshtutorial/themeshdatabase/index.html
2. https://www.youtube.com/watch?v=0lill6yUmk8&t=543s
3. https://www.nlm.nih.gov/mesh/intro_trees.html
4. https://www.youtube.com/watch?v=0lill6yUmk8&t=543s

   
   

   
   

   
   

GENERIC DRUGS: NEEDS AND REGULATION

Tylenol is brand name drugs produced by Johnson & Johnson containing acetaminophen. The cost of Tylenol (extra strength, 100 tablets) is $9.49 whereas acetaminophen (extra strength, 100 tablets) is $2.39. Similarly, the price of Allegra (180 mg, 30 tablets) is $17.99 whereas Fexofenadine (180 mg, 30 tablets) costs $11.99. This is an example of significant change in price for brand drug and its generic counterpart. With the availability of generic drugs, the price drops in 'scalloped curve' fashion. According to Food and Drugs Administration (FDA), Generic drugs are typically 80 -85 % cheaper. This is the reason, countries promotes generic drugs. At the same time, a number of evidences are suggesting that qualities of Generics is being compromised significantly because of aggressive marketing.  

             What are Generic Drugs  

Generic drugs are carbon copy of marketed brand drugs. These are manufactured by any pharmaceutical company by  ensuring that the drug has same chemical constituent, dose & dosage, therapeutic indications, pharmaceutical characteristics, side effects and safety profile with the marketed patent/brand name drugs. Even before getting approval for marketing, generic manufacturer should submit Bio-equivalence study report with the branded one to the regulatory authority of respective country. Many countries including US and India are promoting and regulating production of generic drugs within their own country, to make healthcare affordable to public. Adopting generic drugs for healthcare system might be more important to developing countries with growing health economy.

Global Market for Generics is in Boom

According to BCC Research report 2017, the global market for generic drugs is going to be $474 billion by 2023 from $315 billion (2016), with annual growth rate of 6.8 % during 2018-2023.

Increase in healthcare cost is global burden. Members of OECD (organization for economic co-operation and development) expenses 1.5 % of total GDP only in pharmaceutical products. Till now, generic substitution is found one better method to reduce this cost globally. 

The spectrum of therapeutics covered by generic drugs will be antibacterial, antidepressant, anticancer agents, antiarthritics, cardiovascular drugs and drugs for respiratory diseases. Cardiovascular medications particularly has highest market share because of increasing cardiovascular diseases secondary to changes in lifestyle and eating habit.

Generally pharmaceutical companies spent huge amount of money (in millions) to conduct innovation, discovery, experiments and humans to trials during its development. Also they have to go through vigorous regulatory procedure to get approval for marketing for future use. On contrary, generic drugs are exempt form research and human trial since, they are copied of already marketed one. Regulatory process is also undemanding for them. Food and drugs administrations (FDA) has developed ANDA (abbreviated new drugs application ) in place of NDA, abbreviated because no safety data are need to be submitted.

In 2018 only, the food and drug’s administration of united states approved more than a 1,000  new generic drugs products. Nearby 40 % of all generic drugs available in US market are imported from India, 80 % of active ingredients for both brand and generic drugs come from abroad, India and china majorly.

America makes almost none of its own antibiotics anymore.

They are less expensive, easily available and aggressively marketed. So, people form marginalized community and low socioeconomic status also can afford it.

Generic drugs by competing with branded counterparts, helps to reduce the overall healthcare cost through the globe.

Positive outlook for drugs manufacturer in terms of economic return is catalyzed by increase in prevalence of chronic diseases like: diabetes, hypertension, Alzimer  disease, depression etc. in developed as well as developing countries.

Branded drugs are patented only for certain time limit (generally for 20 years). The space for future marketing for generics has already been established; no need of investment on extensive marketing research. 

Promotional strategy for Generic Uses

Governmental healthcare centers and community hospitals can adopt certain promotional strategies to adopt generic drugs (for both in-patient as well as outpatient), which will help to increase the usage percentage as well as decrease in hospital cost. Study conducted in Gifu municipal hospital, Japan shows that adoption of generic drugs by Hospital increases its use by 9.4% within 1 year time period, The same study found that the dispensing rate as well as price percentage of generic drugs were increased significantly after the adoption. 
The price is variable upon countries to countries, but follows the same pattern while comparing developed versus developing world. The number of factors affect the price determination but, medicine supply chain system and Taxation of that particular country plays the major role. 

Generic manufacturers are misleading scientific and Regulatory community

Although generic manufacturers show Bio-equivalence study report with the patented drugs and get approval, only Bio-equivalence study can’t conform therapeutic range and safety. Specially for drugs with narrow therapeutic index, more evidences are required.

In contrary to general belief of reducing health care price with generic drugs, systematic review on impact of generic substitution on health outcome and economics shows 64% of comparison of economic outcomes suggesting cost to be lower when using original drug. Same study shows 67 % of clinical outcome being similar with the original one.

There is paucity of evidence on effects of generic drugs as de novo therapy for treatment, rather most of uses are confined on substitution therapy from original drugs.

With the massive increase in monetary value, the risk of falsification on data and compromising the quality is also high. This not only jeopardizes the health of consumers but also company’s own market get toppled, once exposed. According to NEW YORK TIMES opinion article by Eban Cathrine published on 11of may 2019, most of generic manufacturers of India supplying drugs to US do not follow industry standard “GOOD MANUFACTURING PRACTICE” and quality is severely compromised. But the regulators are fooled with the falsified and fraud data. Here I have attached small fraction of article as it was

Here I have attached small fraction of article as it was:

Six months into his stint, Mr. Baker visited a plant in Aurangabad run by the Indian company Wockhardt, which made about 110 generic-drug products for the American market. He had one week at the plant to ensure that it complied with the F.D.A. regulations known as “current good manufacturing practices.” Generating and preserving data at each manufacturing step is crucial to those regulations.

On his second day at the Wockhardt plant, Mr. Baker and a colleague caught an employee trying to smuggle out a garbage bag of documents. The documents led Mr. Baker to discover that the plant had knowingly released into Indian and other foreign markets vials of insulin containing metallic fragments. These had apparently come from a defective sterilizing machine. He learned that the company had been using the same defective equipment to make a sterile injectable cardiac drug for the American market. The willful deception there and at other plants so shocked him that he overhauled his inspection methods, with significant results.

Two months after Mr. Baker’s Wockhardt inspection, the F.D.A. banned the import of drugs from that plant into the United States, a potential $100 million loss in sales for the company. Company officials declined to comment on the fallout from the inspection.

Mr. Baker kept digging. Over the next five years, first in India and then in China, he uncovered fraud or deceptive practices in almost four-fifths of the drug plants he inspected. Some of the plants used hidden laboratories, secretly repeated tests and altered results to produce fake data that fundamentally misrepresented drug quality, then submitted that data to regulators.

In some instances, deceptions and other practices have contributed to generic drugs with toxic impurities, unapproved ingredients and dangerous particulates reaching American patients. Some doctors have struggled to stabilize patients who became sicker after they were switched from a brand-name to a generic, or between generic versions. A low-cost drug is not a bargain if it doesn’t work... (for full article, link is attached below)

 This above mentioned fraudulent issue is not only because of lack of professionalism in Indian pharmaceutics but also due to poor regulatory practices of both India and US. Arousal of  The conflict of interest trading and market  sectors is unavoidable, but with proper regulations, adverse impact on public domain is definitely preventable. 

Finally,

In spite of having number of shortcomings, Generic drugs need to be used all over the world. In order to make healthcare cost affordable to every citizen, adopting Generic drugs is one major options available to us till now. At the same time, regulators should be cautious about conflict of interest, vigorous policy and required and meticulous observation of regulations only can insure this  highly economic market. Good quality of drug is what we need not good quality of data.

                                                    THANK YOU !!!

References: 

• https://www.nytimes.com/2019/05/13/books/review/bottle-of-lies-katherine-eban.html?smid=tw-nytimes&smtyp=cur
• https://www.imarcgroup.com/generic-drug-manufacturing-plant
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853161/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519629/
• https://www.nytimes.com/2019/05/13/books/review/bottle-of-lies-katherine-eban.html
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770914/
• https://www.diffen.com/difference/Brand_Name_Drugs_vs_Generic_Drugs