Drug Resistant Tuberculosis

Tuberculosis (TB) is a disease widespread throughout the world caused by Mycobacterium tuberculosis. Despite the strict developed strategies for TB control and significant increase in knowledge of the epidemiology of tuberculosis as well as mechanisms for survival of causative agent of tuberculosis, the disease remains one of the most common and deadly.

Due to developing genetic mutations in any quite large population of Mycobacteria tuberculosis, there are naturally formed mutant strains with drug resistance. At the same time due to development of resistance to one drug, there is greater tendency of mycobacteria to further acquiring resistance to other drugs, which leads to emergence of strains resistant to multiple drugs simultaneously. Patients with multidrug-resistant tuberculosis can be sources for the spread of resistant strains of mycobacteria, which leads to identification of "primary" drug resistance in patients with newly diagnosed tuberculosis.

Multi Drug-Resistant (MDR) TB is treatable and curable by using second-line drugs. However, second-line treatment options are limited and require extensive chemotherapy (up to 2 years of treatment) with medicines that are expensive and toxic.

In some cases, more severe drug resistance can develop. Extensively Drug-Resistant TB (XDR-TB) is a more serious form of MDR-TB caused by bacteria that do not respond to the most effective second-line anti-TB drugs, often leaving patients without any further treatment options.

Additionally, people living with HIV are 20 to 30 times more likely to develop active TB disease than people without HIV.HIV and TB form a lethal combination, each speeding the other's progress. In 2016 about 0.4 million people died of HIV-associated TB. About 40% of deaths among HIV-positive people were due to TB in 2016. In 2016, there were an estimated 1.4 million new cases of TB among people who were HIV-positive.

In 2016, MDR-TB remains a public health crisis and a health security threat. WHO estimates that there were 600 000 new cases with resistance to rifampicin – the most effective first-line drug – of which 490 000 had MDR-TB. The MDR-TB burden largely falls on 3 countries – India, China and the Russian Federation – which together account for nearly half of the global cases.

India has highest burden of both TB and MDR-TB based on estimates reported in Global TB Report 2016. An estimated 1.3 lakh incident multi-drug resistant TB patients emerge annually in India which includes 79000 MDR-TB Patients estimates among notified pulmonary cases. India bears second highest number of estimated HIV associated TB in the world. An estimated 1.1 lakh HIV associated TB occurred in 2015 and 37,000 estimated number of patients died among them.

Control and treatment of MDR-TB became one of the priorities due to awareness of the problem, increase of material and technical facilities as well as distribution of evidence-based medicine. Intensive introduction of alternative and additional treatment strategies is required in order to take control of the serious problem of MDR-TB.

The pipelines for new diagnostics, drugs, treatment regimens and vaccines are progressing, but slowly. Increased investment in research and development is needed.

The treatment of drug resistant TB has always been more difficult than the treatment of drug susceptible TB. It requires the use of second line or reserve drugs that are more costly and cause more side effects. Also the drugs must be taken for up to two years. Fluoroquinolones (FQs) are effective against Mycobacterium tuberculosis and are used in the treatment of multidrug-resistant tuberculosis (MDR-TB). As measured by the in vitro activity against Mycobacterium tuberculosis, the most potent of the currently available fluoroquinolones are, in descending order, moxifloxacin, gatifloxacin, levofloxacin, ofloxacin, and ciprofloxacin. M. tuberculosis clinical isolates that demonstrate high-level phenotypic resistance to fluoroquinolones, which appears to be predominantly due to gyrA mutations, exhibit cross-resistance to all six important fluoroquinolones. Patients with prior exposure to any of the quinolones are likely to develop resistance to other quinolones. Quinolones being broad spectrum antibacterial agents, their widespread and indiscriminate use, often in subtherapeutic doses, is likely to rapidly enhance quinolone-resistant organisms, including mycobacteria. There is rampant use of FQ drugs for undiagnosed respiratory infections in India, which has contributed to the emergence of FQ resistance in M. tuberculosis, which may in turn influence the clinical outcome of MDR-TB patients. For a long time now there has been no new established drug available for MDR TB. At present we are left with few bacteriostatic antitubercular drugs. Reports of quinolone-resistant tuberculosis are constantly pouring in and should act as a warning sign for the bleak future of cases of MDR-TB, because we are rapidly losing a very effective group of drugs for the management of such cases. Moreover, it is recommended that ofloxacin is phased out from MDR-TB regimens and ciprofloxacin is never used due to the limited evidence for its effectiveness.

#mdrtb #tuberculosis #antituberculosis #drugs #hiv #tb #treatment

6th Anniversory

History of Clinical Research Regulation in India

All regulatory bodies has the responsibility to provide access to the safe, effective and quality, medication to their people.  The Central Drugs Standard Control Organization and Drug Controller General of India are bequeathed to protect the citizens from the exposer of unsafe medication. Either it is through clinical research or marketing. The growing clinical research after the product patents rights for the pharmaceutical industries as per the trade related aspects of intellectual property rights agreement and adverse drug reaction monitoring, rights and safety of Patients, compensation after adverse event clinical research and of the marketed drugs have raised many ethical and regulatory issues.

The regulatory measures has to be dynamic and ever evolving in consonance with the developing technologies. Indian regulations have also experienced this a lot of change from british era. Last three years were little disturbing and this lead to loss of opportunity and mistrust in Pharmaceutical domain. But now regulation is well organized, systematic and compliant to international regulatory standards for pharma products, medical devices, traditional herbal products and cosmetics.

Now question arise why Indian regulators took so much time in this reform? To understand this we have to understand the history of Clinical research. It started in British Raj when most of the drugs were imported from foreign countries. Post First World War, the demand for drugs had increased tremendously and that led to the cheap, substandard, spurious and adulterated drugs into the market. To control in market, Government passed the Poisons Act 1919. This Act regulates possession of substance or sale of substances as specified as poison. The Poisons Act was followed by The Dangerous Drugs Act 1930. This act regulates the opium plant cultivation, manufacture and possession of opium, its import, export, tranship and sell of opium.

In response to widespread ‘Gigantic Quinine Fraud’; the Government, then, formed a Drug inquiry committee under Sir Ram Nath Chopra also known as ‘Chopra Committee’ whose recommendations later on tabled amidst growing protest in legislative assembly as ‘The Drug Bill’ later on amended to the Drugs and Cosmetic Act 1940 (D and C Act) and Drugs and Cosmetic rules of 1945. This also established the Central Drugs Standard Control Organization (CDSCO), and the office of its controller, the Drugs Controller General (India) (DCG(I)).  The CDSCO in the Directorate General of Health services, is a division in Ministry of Health and Family welfare, Government of India, headed by Drug Controller General of India (DCGI). It has four zonal, three sub-zonal and seven port/airport offices and six laboratories to carry out its activities. The Drugs and Cosmetic Act, 1940 came into force from 1st April 1947. In year 1948 Pharmacy Act came into existence to regulate the profession of pharmacy in India and in 1955 Drugs and Magic Remedies rule came into existence for control the claim and advertisement.

In 1962, government extended the regulatory provisions to the cosmetics, and finally the Act came to known as Drugs and Cosmetic Act 1940. Drugs and Cosmetic Act has been divided in Chapters, Rules and Schedules and is amended from time to time to control the safety, efficacy and quality of the drugs. It is an act to regulate the import, manufacture, distribution and sale of the drugs and cosmetics. Manufacture and sale is under the respective states governments and union territories through their respective drug control organization, whereas setting standard, import, marketing authorization and monitoring of adverse drug reactions of a new drug is under Central Government. Under Chapter Two of this Act, one statutory board and a committee have been framed called Drugs Technical Advisory Board (DTAB) and Drug Consultative Committee (DCC) separately for Modern Scientific System of Medicine and Indian traditional system of Medicine and a provision of Central Drug Laboratory at Central Research Institute, Kasauli for testing drugs has been made in this act. DTAB comprises of technical experts who advises central and state governments on technical matters of Drug regulation. Amendment, if any, to Drug and Cosmetic are made after consulting this board.

During this period the market share was dominated by multinational companies and very few Indian manufacturers were present. The Indian Pharmaceutical industry was in an early stage of growth. Focus for pure research and development was very little due to lack of patent protection. Due to very high import dependency on drugs, the cost of drugs was very high as well as market availability was comparatively low. In 1955, government has passed Drugs Prices Control Order, 1955 (DPCO) (under the essential commodities Act). Due to which many essentials drugs were unavailable in Indian market. To save Indian companies and to provide medicine Indian population at low cost Indian government introduced Indian Patent Act of 1970. This new act replaced the Indian Patents and Designs Act of 1911.   

The Indian Patents Act of 1970 originally had provisions for ‘process’ patents only. Now, local companies began manufacturing products/ drugs using different manufacturing process by reverse engineering. Due to this new drugs were available cheaply as well as many more substitute drugs were available in the market against costly imported new drugs. This has resulted in 1) increase the exports to countries like Russia, Africa, China, and South America. 2) Export of Bulk drug post patent expiry.

In 1994, Government signed the agreement on Trade Related Aspects of Intellectual Properties (TRIPS) to provide minimum protection to the Intellectual Property by the member states of World Trade Organization (WTO). India amended the Patent (Amendment) Bill before 2005 and extended its weak process patent to strong TRIPS competent ‘Product’ patent system for pharmaceutical products.

The Indian government, realizing the potential of clinical research for new therapies, has modified and amended Schedule Y to the Drug and Cosmetics Rules of 1945. Schedule Y establishes a set of guidelines and requirements for clinical trials. However, Schedule Y was written with the generics industry in mind but increase entry of foreign pharmaceutical companies after the introduction of strict patent rules in the area of clinical research led the government to introduce many changes. The government recognized the importance of their regulation and thus developed Ethical and Regulatory Guidelines. The Indian Council of Medical Research (ICMR) issued the Ethical Guidelines for Biomedical Research on Human Subjects in 2000 and CDSCO released Indian Good Clinical Practice (GCP) guidelines in 2001.

With the application of Product patent in 2005, recognizing individual's innovations through the Trade Related Aspects of Intellectual Property Rights (TRIPS) agreement, which India had signed in 1995, became effective. Indian companies began to respect Intellectual Property rights, consistent with international standards. With the increasing faith in the system, companies flooded the market and more global trials came. Lately, to decrease the review time of application from 16 weeks to 10 weeks the CDSCO has introduced the fast tracking of clinical trials in 2006. The DCG (I) created two categories of applications; Category: (A) Those also being conducted in countries with competent, mature regulatory systems, and Category: (B) Everything else.

Trials that fell into category A (received approval in the U.S., Britain, Canada, Germany, South Africa, Switzerland, Australia, Japan and countries in the European Medicines Agency (EMEA)) would be eligible for fast tracking in India, with approval taking no more than two to four weeks. Trials in category B would fall under more scrutiny; with approval taking 12 weeks once an application is considered under Category B, it, in any case, cannot be shifted to Category A. Nearly all global trials are in the Category A.

In 2011, Drugs and Cosmetics (First Amendment) Rules was implemented. It mandates registration of Clinical Research Organization (CRO) for conducting Clinical Trials (CT). Schedule Y suggests requirements and guidelines for registration of Clinical Research Organizations. Although amendment to Schedule Y, registration of Contract Research Organizations, registration of Clinical Trials, Speeding up review process, Pharmacovigilance (PV) programme for India and Inspection of clinical trial sites have been started. However due to casual approach in marketing approval, unethical steps taken by some pharmaceutical companies and medical practitioners has reiterated the need to amend the regulations. DCGI slowed down their actives related to approval of studies as per the guidance of Supreme Court and Government of India and started concentrating on the regulatory framework.

DCGI further amended the policies for to improve the quality of clinical research. It took three years to design this:

• Sponsors, investigators, the regulator and Ethics Committees are responsible for ensuring that the design of placebo-controlled trials is appropriate, efficient and ethical;
• The Ethics Committees will have to be registered under DCGI
• Investigators are limited to working on a maximum of three trials simultaneously;
• If a new chemical entity is approved in the innovator or “well-regulated” country for a disease prevalent in India, and the clinical trial included Indian participants, CDSCO advises that “approval should be sought from CDSCO” and “these NCEs should be marketed in India speedily.” CDSCO also specifies that if a foreign trial included Indian participants, the number would have to be “adequate” for considering approval of the drug in India;
• Waiver of clinical trials in Indian populations with drugs already approved outside India will only be considered in cases of national emergency, extreme urgency and epidemic, and for orphan drugs for rare diseases and drugs for conditions/diseases for which there is no therapy;
• Generics and biosimilars marketing “in other countries like USA” for over four years and have a “satisfactory report” can be approved in India after abbreviated trials;
• Consideration of new drug applications will take into account ethnic differences in metabolism etc.;
• If two or more countries remove a drug from their market on the grounds of safety and efficacy, the continued marketing of the drug in India “will be considered for examination and appropriate action” by CDSCO; and
• Manufacturers, sponsors and CROs are advised to provide compensation for any drug-related anomaly detected at a later stage.
• CDSCO is also re-organizing the structure of the committees involved in the drug approval process.  The New Drug Advisory Committees will now become the Subject Expert Committees, whose recommendations will be reviewed by a newly formed Technical Review Committee (TRC).  The TRC will be under the direction of the Directorate General of Health Services (DGHS), which will draw the membership of the committee from experts in such areas as clinical pharmacology, clinical toxicology/ pathology, and scientists involved in drug development. 

As we all understand that regulatory improvement is continual process and no system is perfect. DCGI still needs a lot of improvement to ensure safety and wellbeing of Indian population along with promoting introducing new product.

Medical device clinical trials

Unlike Pharmaceutical technologies, there are no dedicated established centers- MEDICAL DEVICE CROs in ample amount which could satisfactorily facilitate a medical device product evaluation and commercialization nor clinical evaluation guidelines in medical devices sector i.e. ISO-14155, ICH-GCP in adaptation oriented towards medical devices are taught in institutions so as to enable the students take such projects and come up with an excellent guideline document for producing local, national or global impact.

Medical device related health economics: The education could be imparted with Intended Learning Objective (ILO) of providing insight to economic evaluation of clinical effectiveness or diagnostic accuracy of medical devices with respective cost dimensions. This may comprise projects like preparation of costs database, estimation of budget for reimbursement schemes on medical device failure and so on.

Medical Technology Surveillance: There is little guidance available in field of post-marketing surveillance of medical devices especially in India. Unlike PvPI and hemovigilance, no such programme is available for medical devices. A model or strategy for the same could be invoked for purpose of brainstorming in students.

Regulatory Affairs and Standardization: Understanding how to put boundaries to innovations while their diffusion is something highly expected to be taught. It is fact that MATLAB,LABVIEW related digital image processing projects are promoted always but no project is seen which might have explored ethical issues related pros and cons associated with image processing i.e. violation of PNDT act, misdiagnosis of any abnormality or disorder. Moreover, there is less education provided on CE marking, Medical device standards, Medical device testing.

Intellectual Property Rights: No course I came across so far incorporates this aspect from project perspective i.e. project on assessing IPR issues faced by device manufacturers, comparison of device patentization framework of different countries, petty patents.

Bridging translational gap: It is hard fact that even after outstanding project model, there is no support in terms of how to accelerate it for professional growth with commercialisation purposes. Most of projects are just for sake of completion and not with realization and/or continuation of further journey. Such lacking in system is also proposes threat of plagiarised projects (ready-made models/circuits in markets) or “frog-in-well” approach during project.

I believe if this type of thinking could be done "apriori", then biomedical engineering’s value could be realised like never before. And also I believe that these aspects, when ingrained in curriculums, it would be “pride” rather than “speechlessness” or “cluelessness” when somebody would ask the reason for choosing this branch.

I would be happy to see as many as comments and suggestions for this post.

Let's start our journey for evidence-based-medical device research and development !!