Without a magic wand, India cannot eliminate TB by 2025

GeneXpert

Only 93,000 MDR-TB cases have been diagnosed till 2015 in India.

At the end of 50 years of tuberculosis control activities, the disease remains a major health challenge in India. As per new estimates, the number of new cases every year has risen to 2.8 million and mortality is put at 4,80,000 each year. These figures may go up when the national TB prevalence survey is undertaken in 2017-18. Against this backdrop, the Ministry of Health and Family Welfare, in its national strategic plan for tuberculosis elimination (2017-2025), has set a highly ambitious goal of “achieving a rapid decline in burden of TB, morbidity and mortality while working towards elimination of TB by 2025.”

Though the Revised National Tuberculosis Control Programme (RNTCP) has treated 10 million patients, the rate of decline has been slow. Providing universal access to early diagnosis and treatment and improving case detection were the main goals of the national strategic plan 2012-17. But the RNTCP failed on both counts, as the Joint Monitoring Mission report of 2015 pointed out. Going by the current rate of decline, India is far from reaching the 2030 Sustainable Development Goals — reducing the number of deaths by 90% and TB incidence by 80% compared with 2015. Yet, the latest report for TB elimination calls for reducing TB incidence from 217 per 1,00,000 in 2015 to 142 by 2020 and 44 by 2025 and reduce mortality from 32 to 15 by 2020 and 3 per 1,00,000 by 2025.

Incidentally, nearly 50% of people in India are latently infected with TB. According to CDC, 5-10% of infected people will develop TB disease at some time in their lives. “About half of those people who develop TB will do so within the first two years of infection,” the CDC says. With the latently infected people acting as a reservoir, it will be nearly impossible to eliminate TB in India by 2025.

Radical approaches are needed to come anywhere close to reaching these ambitious targets. Most importantly, the TB control programme plans to do away with the strategy of waiting for patients to walk in to get tested and instead engage in detecting more cases, both drug-sensitive and drug-resistant. The emphasis will be on using highly sensitive diagnostic tests, undertaking universal testing for drug-resistant TB, reaching out to TB patients seeking care from private doctors and targeting people belonging to high-risk populations.

The other priority is to provide anti-TB treatment — irrespective of where patients seek care from, public or private — and ensure that they complete the treatment. For the first time, the TB control programme talks of having in place patient-friendly systems to provide treatment and social support. It seeks to make the daily regimen universal; currently, the thrice weekly regimen is followed by RNTCP, and the daily regimen has been introduced only in five States. There will be a rapid scale-up of short-course regimens for drug-resistant TB and drug sensitivity testing-guided treatment. In 2013, India “achieved complete geographical coverage” for MDR-TB (multi-drug-resistant tuberculosis) diagnosis and treatment.  Yet, only 93,000 people with MDR-TB had been diagnosed and put on treatment till 2015; several MDR-TB cases are simply not diagnosed.

What next?

Though Bedaquiline, the drug for people who do not respond to any anti-TB medicine, is provided in six sites in the country, the number of beneficiaries is very small. It has been a battle to get the drug for treatment, as in the case of an 18-year-old who had to approach the Supreme Court for help. Yet, the report envisages a countrywide scale-up of Bedaquiline and Delamanid.

In a marked departure, the report underscores the need to prevent the emergence of TB in susceptible populations. One such segment is those in contact with a recently diagnosed pulmonary TB. Incidentally, active-case finding is already a part of the RNTCP programme but rarely implemented. It wants to increase active case finding to 100% by 2020. Since RNTCP expenditure has increased by 27% since 2012 and is inadequately funded, the Ministry proposes to increase funding to ₹16,500 crore.

Acknowledging that the business-as-usual approach will not get the Health Ministry anywhere close to the goals, it has earmarked critical components that will be addressed on priority. These include sending customised SMSes to improve drug compliance, incentivising private doctors to notify cases and providing free medicines to patients approaching the private sector, facilitating nutritional support to TB patients, including financial support, rewarding States performing well in controlling TB, and using management information systems to monitor all aspects of TB control. “The ultimate impact of this national strategic plan will be transformational improvements in the end TB efforts of India,” the report says. It plans to take a “detect-treat-prevent-build approach” in its war against TB.

Published in The Hindu on March 19, 2017

Why is TB bacteria not on WHO’s deadly superbug list?

Pharmacy - Photo R. PrasadOf the estimated 10.4 million new tuberculosis cases globally in 2015, nearly 0.5 million estimated cases were multidrug-resistant (MDR) TB cases. Another nearly one million were resistant to rifampicin drug alone. India accounted for 2.84 million new cases in 2015, of which 79,000 had MDR-TB. There were 1.4 million TB deaths worldwide in 2015.

For the first time in nearly 50 years, two new drugs, bedaquiline and delamanid, were approved by the US Food and Drug Administration for use in MDR-TB cases. The accelerated approval of bedaquiline by the FDA was based on interim Phase IIa data. The lack of large-scale safety data and the paucity of effective TB drugs, especially for MDR-TB, are the reasons why the World Health Organisation insists that the drug be used only when all “options to treat TB using existing drugs have been exhausted”. The WHO also makes it abundantly clear that all efforts should be taken to avoid TB bacteria from developing drug resistance to bedaquiline as a result of misuse.

Despite the gravity of the situation and a near-empty drug chest to fight TB in India, a WHO list, released on February 27 of drug-resistant bacteria that pose the “greatest threat to human health” and for which new drugs are desperately needed, has no mention of Mycobacterium tuberculosis, the bacteria which causes TB.

Not a priority pathogen?
This is the first time that the WHO has released such a list and the prime objective of listing the “priority pathogens”, in its own words, is to “guide and promote research and development of new antibiotics… and to address the growing global resistance to antimicrobial medicines”.

The list is divided into three categories — critical, high and medium —based on the urgency of need for new drugs. While the WHO reasons that malaria and HIV have not been included in the list as they are not bacterial infections, it cites a completely different reason for not including TB bacteria. According to the WHO, TB bacterium was not included in the list as it is already targeted by other “dedicated programmes”.

In a strongly worded open letter to WHO’s Director-General Dr Margaret Chan, The International Union Against Tuberculosis and Lung Diseases, or simply The Union, says it is “outrageous” that Mycobacterium tuberculosis was not considered for inclusion as it is “already a globally established priority for which innovative new treatments are urgently needed”.

“This explanation defies reason [and] contradicts the stated intent of the global priority pathogens list’s methodology to define the list,” the letter reads. “TB’s exclusion sends the false and counterproductive message that drug-resistant TB is not an urgent public health threat,” the letter says. It also send a strong message to policymakers to “deprioritise TB research”, it adds.

Meets criteria for inclusion
The reason why The Union has reacted so strongly is because the TB bacteria meets each of the 10 criteria used for inclusion in the list — how deadly the infections are, the number of infected people in a community, prevalence of resistance, how easily the bacterium spreads from one person to another, options to prevent the infection in hospital and community, treatment options and whether new drugs are already in the R&D pipeline.

The WHO states that new antibiotics most urgently needed will never be developed in time if it is left to market forces alone. This is best demonstrated in the case of TB. It took nearly 50 years for new TB drugs to be approved for MDR-TB and not a single antibiotic has been developed for drug-sensitive TB in half a century.

Since the WHO has stated that the list has been developed to allow periodic revisions and inclusions of other pathogens, including viruses and parasites, The Union wants the TB bacteria to be included in the list before the WHO publishes the full protocol and results by the end of May 2017.

Published in The Hindu on March 5, 2017

Pilot testing of bedaquiline drug on TB patients to start soon

BedA pilot programme to test the toxicity, particularly cardio-toxicity, of bedaquiline drug (used for combating multidrug-drug resistant TB) in the Indian population, assess its ability to achieve culture conversion and check the operational feasibility of using the drug to treat MDR-TB patients would start in India by the end of this month or on World TB day.

Six hundred MDR-TB patients would be enrolled in six institutions — two in Delhi, and one each in Mumbai, Ahmedabad, Guwahati, and Chennai — to study the suitability of the drug for the Indian population. Only those patients who are resistant to both rifampicin and isoniazid, the first-line TB drugs, will be enrolled in the programme.

In its interim guidance, the World Health Organisation (WHO) had laid special emphasis on closely monitoring the response to treatment and informing the patients of the benefits and possible harms of the drug.

The pilot programme would last for six months. As per the WHO’s recommendation, bedaquiline will be given to the patients in addition to the regular multidrug treatment regimen.

Unlike clinical trials, the six institutions will not enrol a certain number of patients each.  Instead, patients willing to participate in the programme will be enrolled in any of the institutions on a first come first served basis.

The pilot implementation was supposed to have been launched on January 29 and then later pushed to February 4.  Enrolment of 600 MDR-TB patients is expected to take time as second-line drug susceptibility testing has to be first carried out in those willing to participate and their informed consent has to be taken. The toxicity of the drug may delay the enrolment, a senior official told The Hindu.

Phase III trials using this drug have not been completed yet and based on Phase IIb trials done outside India, the drug was found to disturb the functioning of the heart (cause abnormal and potentially fatal heart rhythm) and cause adverse drug reactions in the liver. Most importantly, unexplained increase in mortality was reported during the trials.

Published in The Hindu on February 19, 2016

Clinical trials on child-friendly bedaquiline MDR-TB drug for children initiated

“Before the BPCA [Best Pharmaceuticals for Children Act] and the PREA [Paediatric Research Equity Act] became law, more than 80 per cent of the drugs approved [by FDA] for adult use were being used for children, even though the safety and effectiveness had not been established in the latter. Today that number has been reduced to about 50 per cent,” a FDA blog post notes.

The effects of BPCA and PREA are already beginning to show. Janssen Pharmaceuticals, whose new drug (bedaquiline) was approved by the FDA last year for use in adults with MDR-TB disease, has already initiated steps to produce a paediatric version.

“Janssen is conducting what’s called a ‘bioavailability study’ where the pharmacokinetic and other parameters (such as taste) of two new paediatric formulations of bedaquiline (granules or water dispersible tablets) would be compared with the pharmacokinetic parameters of the current adult tablet formulation,” Daniel De Schryver, Global Communications Leader, Infectious Diseases and Vaccines, Janssen Research & Development, Belgium stated in an email to this Correspondent.

“Such a trial is normally conducted in healthy adults,” Schryver noted. “Once a suitable paediatric formulation is identified, a trial will then be conducted in paediatric MDR TB patients (up to age 18 years) to determine the safety and efficacy of bedaquiline in these patients taking either the identified paediatric formulation or the adult tablets, where appropriate.”

Once it is tested in adults, children of different age groups would be studied, starting with the oldest group — 12-18 years. This age group would be given the adult formulation as very often they tend to develop adult-type TB disease. “Based on the results from this older cohort, the trial would then proceed to the next cohort, using an age-appropriate formulation, and so on until the youngest group (as young as 6 months of age) is reached,” he explained. It is not clear when paediatric drug formulation of bedaquiline would become available for the youngest age group.

The three age groups of children (who tend to develop paediatric MDR-TB disease) to be studied are 6–12 years, 2–6 years, and 6 months–2 years respectively.

There is a compelling need to conduct clinical trials in children even when the safety, dosage and efficacy of the drug have been studied in adults. One needs to take a few steps backwards to understand this.

By default, the amount of TB drug does “not reach the same concentration in the blood of children compared with adults” for a given mg/kg body weight dosage. This results in under-dosing in children. The only way to overcome this is by increasing the dosage of TB drugs (mg/kg body weight) given to children. WHO revised upwards the dosing of TB drugs for children only in 2010!

“More science has been done and hence we are able to understand why we are not able to treat children correctly,” Dr. Denis Broun, Executive Director of UNITAID said to this Correspondent over phone from Geneva while explaining why it took a long time for WHO to revise the dosing for children. “Not that it [science of dosing] was bad before, it has become better now.”

And since the drug dosage for children has been increased, clinical trials to study pharmacokinetics and bioavailability have to necessarily be undertaken.

If the two FDA rules make it mandatory for Janssen to produce paediatric formulations of bedaquiline, UNITAID’s grant of $16.7 million to TB Alliance in December last year to accelerate the development of paediatric TB regimens has provided an additional impetus.

“Developing paediatric [TB] drugs is a not a big market for pharmaceutical companies. Have faced this in the case of HIV too,” Dr. Broun said. “The point is to put money upfront so companies would create new drugs.”

“We are working with Janssen to speed up the availability of the paediatric formulation of bedaquiline, which was approved for the treatment of MDR-TB in adults last year,” Dr. Mel Spigelman, President and Chief Executive Officer of the Global Alliance for TB Drug Development (TB Alliance) said in email to this Correspondent. “TB Alliance’s work … will aim to reduce the lag time between adult and paediatric formulations of new drugs, accelerating the availability of new TB drugs in paediatric form.”

(The Correspondent is a recipient of the 2013 REACH Lilly MDR-TB Partnership National Media Fellowship for Reporting on TB)

Published in The Hindu on December 14, 2013

Child-friendly, first-line TB combination drugs will be available in 2016: Dr. Mel Spigelman

Dr. Mel Spigelman - Photo TB Alliance

Dr. Mel Spigelman, President and Chief Executive Officer of the Global Alliance for TB Drug Development (TB Alliance) is regarded as one of the world’s leading experts in tuberculosis and TB drug development. He was instrumental in forging key organisational partnerships and building the pipeline of TB drug candidates when he was the Director of Research & Development at TB Alliance. In an email to me, Dr. Spigelman explained the various facets of paediatric TB drug development.

Is there a greater involvement by drug companies in producing paediatric TB formulations after UNITAID provided a grant of $16.7 million and USAID also contributed funds?

The goal of the grant is to develop first-line TB treatments designed for children, in the proper doses and formulations, but also to help catalyse paediatric TB drug development among pharmaceutical companies through a variety of incentives. More accurately defining the market, clarifying the regulatory pathways for new products, and addressing barriers to entry for manufacturers are all within the scope of our work, and will help bring new partners into the field.

We’ve already engaged and entered into collaborations with interested generic manufacturers, including Svizera, which will help improve access to treatments. It’s also important to note that TB Alliance’s work under this grant will aim to reduce the lag time between adult and paediatric formulations of new drugs, accelerating the availability of new TB drugs in paediatric form. For example, we are working with Janssen to speed up the availability of the paediatric formulation of bedaquiline, which was approved for the treatment of MDR-TB in adults last year.

Is this a big amount to attract pharmaceutical companies to get into paediatric drug development?

The funding provided in the grant is designated for a discreet set of projects; it is not a pot of money to be given to pharmaceutical companies to work on paediatric TB drug development in a broader sense.

The impact of the work from this grant, in addition to bringing new products to the market, is to create an environment conducive to sustained and productive efforts in the field of paediatric TB drug development. This will require the involvement of pharmaceutical companies, as well as numerous other sectors including regulators, clinical researchers, Ministries of Health and Finance, drug sellers and even patients and their families. By prepairing the market for these products, we intend to lower the barriers for the necessary parties to work toward improved TB treatment for children over the long term, beyond the life of this grant.

Has any Indian pharmaceutical company shown interest in developing fixed-dose combination drugs for children?

The current paediatric TB fixed-dosed products sold through the WHO’s Global Drug Facility are produced by Indian pharma companies (Lupin and Macleods). TB Alliance has already entered into an agreement with Svizera to produce new first-line treatments in the doses now recommended by WHO and we are in discussion with other Indian pharmaceutical companies.

Because of their experience, Indian manufacturers are among those for whom we see a likely role in producing new TB drug products for children.

How long would it take to come up with fixed-dose combination drugs for first-line TB drugs? How long would a clinical trial take and how many subjects are needed to test bioavailability?

One of the significant challenges to the development of new paediatric TB treatments is the need for additional clarity on what is needed for such a product to receive approval by the various regulatory authorities around the world. These studies can take 6 to 18 months to complete. The quantity and scope of these studies required for regulatory approval can vary by country. We are working to collect that information and disseminate it widely, so that those with the capacity to work in this space have a clear understanding of what needs to be done, how to do it, and what regulators need to see to make approval decisions.

That said, we expect that the first wave of new, simpler, fixed-dose combinations for children will be available in 2016, fulfilling a significant need.

Since we need several dosages to cater to different weight bands, will the cost of drug development become expensive?

Fixed-dose combinations of current first-line TB treatments are weight-banded for both adults and children. The improved first-line TB treatments for children that will be made available as a result of this grant will be weight-banded as well. Dose-ranging studies are underway for the small group of newborns for whom this information is not already available. Dispersible tablets allow the same tablet to be dissolved in water or other liquid; different amounts are then given for each of the different weight groups, which is a cost-effective means of delivery.

When do you think the first-line, fixed-dose combination drugs would become available?

Our goal is to have optimised formulations of existing first-line treatment for children available to be sold through a global procurement agency by 2016, with a phased market rollout to follow.

Are there any attempts to come up with child-friendly second-line drugs? Cancombination drugs be produced for second-line drugs, as the choice of drugs depends on the drug sensitivity test results?

There are a number of obstacles to developing fixed-dose combinations of the current second-line drugs for children, including the fact that not all the second-line TB drugs are administered the same way. Kanamycin and capreomycin are delivered via injection, for example. While many groups advocate for drug developers to develop child-friendly formulations of the current second-line drugs, in the long run, we need new drugs to treat MDR-TB. Only then can we shorten the long treatment time (up to two years) and avoid the many toxicities that are associated with today’s MDR-TB treatments. Compared with adults, children respond better to second-line treatment — but no person should have to endure such a difficult regimen. With the development of new regimens for the treatment of drug-resistant TB with hopefully new drugs to which there is no pre-existent resistance, combination products will become readily available for treatment of what is now considered drug-resistant TB.

How long would it take and how many children are needed to undertake bioavailability of fixed-dose combinations drug trials?

The number of children to be enrolled and the timeline for either a bioavailability or bioequivalence study are agreed upon between the manufacturer and the regulatory authority reviewing the product for market authorisation/approval.

Will such trials have a control group that receives regular dispersible drugs/syrups?

Efficacy trials that require control groups are not needed to obtain regulatory approval for improved first-line paediatric drug formulations already in the market. Mostly bioequivalence and bioavailability studies on fixed-dose combinations are needed, which compare the combination tablet with the single drug and make sure they deliver the same dose.

Don’t these dispersible drugs have their own problems — requiring refrigeration and having a shorter shelf life?

The manufacturer has to demonstrate the stability of the drugs they make. Today’s FDCs do not require refrigeration, but must be kept at below 30 or 40 degrees C. They have a shelf life of 2 to 3 years.

But current treatments do have substantial problems. The most significant problem, as it relates to children specifically, is that current treatments are not manufactured in doses that match the WHO guidelines for paediatric TB treatment, which were issued in 2010. Therefore, in practice, providers and caregivers must crush or cut adults pills to reach the proper dose.

In addition, the length of treatment and side effects are a burden to [both] children and the adults caring for them. Parents must transport their child to receive treatment, ensure the child completes treatment, and often administer the treatment over six months or longer.

As part of the effort to develop new first-line TB drugs specifically designed for children, one of the options we are exploring is the more preferred formulations for such drugs — dispersibles, sprinkles, syrups, etc. Different formulations may have different profiles in terms of storage requirements and other characteristics with logistical implications for storage, manufacture, and distribution.

When the shelf life is shorter, can countries be able to procure drugs in large quantities and stock them for a long time? Will drug stock-out not become a regular feature?

Stock-outs of drugs can be caused by many factors, but a critical component is ensuring that the forecasted need for the drugs is close to the actual need. When planning, National TB Programmes include a buffer stock in any order to ensure that if the forecast is a little off, there are sufficient products. However, if the projected need is miscalculated, then stock-outs can occur. A longer shelf life can help prevent a stock-out even when forecasts are inaccurate.

Ensuring access to the treatments we develop is a critical priority for TB Alliance. Among the attributes we consider when determining the viability of a product are its stability and shelf life. We do not develop products or formulations of products which we believe would impose new or significant challenges on storage and administration of treatment.

The child-friendly combination drugs are for those younger than five years. Do we know the disease burden in this age group?

For clarification, child-friendly TB products are limited to children under 30 kg which limits the use of the drugs by weight and not by age. Depending on the region of the world, median weights for different age groups can vary. Children five years and under are a critical group, since they are most susceptible to becoming sick and dying from TB; however, all children need improved TB treatment.

Determining the actual number of paediatric patients, including those who are younger than five years old is a challenge, given the overall challenges in diagnosing paediatric TB. However, as part of this grant and in conjunction with other groups such as WHO, we are working to develop a better estimate of this cohort than has previously been available.

How can formulations be developed when pharmacokinetics of the first-line TB drugs are not known for children under two years of age?

There are only a few studies in this younger population that provide evidence for the 2010 WHO recommendations, and WHO recommended additional studies in the smallest children to be sure of the correct dose. We do know that this group absorbs, metabolizes and excretes certain drugs differently. These differences may or may not require separate recommendations for first-line treatment. Rather than have caregivers guess the correct dose for these children, the project will obtain pharmacokinetic data of the first-line TB drugs for children less than 12 months old where there are no data, and publish recommendations for this group to ensure that all children are treated optimally and are cured. There is a fairly good understanding of dose for children above 5 kg.

Since we don’t know the true disease burden in those younger than five years, are we not underestimating the disease burden and hence the market size for paediatric drugs?

The current market size is based on the number of treated patients, whereas the potential market size involves disease burden, which includes both treated and untreated patients. One of the efforts of this grant is to determine a more accurate and complete estimate of the global paediatric TB market, current and potential. We are working with partners to develop a better model for estimating these numbers, and have many studies, both underway and planned, that will yield additional information that will enable the further refinement of that model.

We realise there is much that will improve our estimates, including identifying where children are treated and where they are lost in the diagnosis and treatment process. Importantly, systems to improve reporting of cases to the National TB Programmes need to be expanded and improved to ensure that all children with TB are counted. Some may be seeking treatment in the private sector and therefore not be counted. Also, it is thought that a significant amount of childhood TB is actually misdiagnosed, or mis-categorized and that a substantial amount of childhood TB “hides” in other morbidity categories, such as pneumonia.

What delayed the development of drugs for children — the unknown disease burden and hence unknown market size, unprofitable business, lack of interest as children do not spread disease, difficulty in doing trials, resources to conduct trials, unknown pharmacokinetics in young children (<5 years)…?

I think there are a number of factors that have contributed to the stagnation of activity in this field.

Lack of financial incentive: This dynamic is seen across all neglected disease areas, and is a major obstacle to engagement in TB in general.

Lack of understanding of regulatory approval requirements and mechanisms: A lack of clarity about how best to obtain regulatory approval in various regions for new TB drugs for children serves/served as a powerful disincentive to engagement.

Incorrect information regarding burden/market size: Most experts believe the global paediatric TB burden to be larger than official estimates state. This underestimation undersells both the urgency and level of return in addressing the problem.

Insufficient information regarding the treatment recommendations: Manufacturers were told of a new dose form shortly after they had developed the current form. As a result, they were not confident that the dose recommendations would not change again and they were unwilling to commit to development of a new product.

Traditional research strategy: When it comes to new drugs in development, new drugs are traditionally developed for adults first and then tested in children, of decreasing age, for ethical reasons. Having only been rekindled roughly a decade ago, it took several years for the pipeline of new TB drug candidates to reach the point where traditional drug development processes dictated that it was time to turn attention to paediatric patients.

Complacency: Greater advocacy around such issues, and TB in general, is needed to pressure all stakeholders to engage in this activity.

As a result of all this, a comprehensive approach, with a multitude of partners, is needed. TB Alliance appreciates UNITAID’s grant in this area, which allows the organisation to kick-start this work. Clearly, more support is needed to see all of it through and end the neglect of children with TB.

What is the knowledge-sharing initiative that TB Alliance has undertaken? How will it improve the development of drugs?

TB Alliance intends to share all the lessons and insights learned throughout this endeavour widely available to those in high TB burden countries managing the TB epidemic, to the manufacturers, to new drug developers as well as to the general public. These efforts will take many forms, including a web portal that will be launched early next year where these groups can seek a range of information and gain answers to their questions. In reshaping the information landscape, we hope to lower the barriers for many to participate in advancing new treatments for children.

Will the regulatory requirements be the same for paediatric formulations as for adult formulations?

Some of the requirements are expected to be the same, whereas others will be different. Clarifying the regulatory pathway for new paediatric TB treatments is a key part of this initiative. We are in conversations with leading regulatory bodies and experts around the world and will communicate what we learn though both discussion and practice. It is envisioned that many of the lessons learned through the development of improved first-line TB treatments for children will translate to a clear and accelerated path for the development and approval for children of the new TB drug candidates just approved for adults or anticipated to reach market in the next few years.

The UNITAID grant includes defining the disease burden. But considering that 85-90 per cent of young children (<5 years) are smear-negative, how can you get to know the disease burden, even an approximation?

Children, smear-positive and smear-negative, are being clinically diagnosed; we just cannot confirm those diagnoses with sputum in smear-negative patients. Now, children are lost in the diagnostic/treatment process so there are significant complexities…and we intend to use various data and analyse that data in many different ways to reach better estimates. The model developed to estimate the global TB burden will be a living tool, and many studies of different types are scheduled and already underway to feed information into that model to continually refine and improve its accuracy. Examples of the types of data that can reveal insight into this question are: inventory studies of treatment programmes, investigation into practices of private treatment providers, sales figures of TB drugs, and many others.

What is the incentive for drug companies to keep producing child-friendly drugs for the ‘poor’ people who can’t be charged a premium price?

When any organisation collaborates with TB Alliance on product development work, we insist they agree to make any products developed affordable to those who need them. However, we recognize that to maintain steady supply of a product, companies need to avoid losing money on the product; however, the price of these treatments will still be affordable. All around the world TB medicines are made available free of charge to patients via the National TB Programmes. This arrangement is often possible with the commitment of donors and governments who recognise the need to invest in life-saving drugs for children with TB.

TB Alliance’s involvement lowers the technical barriers, as we are working in partnership to help organisations tackle the challenges they face in this area. Additional incentives include the moral impetus of such work, potential innovative financing mechanisms, a likely larger than previously expected market for such products, and a simple procurement model — large quantities will be bought from certain core suppliers, such as the WHO’s Global Drug Facility (GDF).

Published in The Hindu on December 12, 2013

Is the new TB drug already being misused?

Mycobacterium - Photo -  CDC

Bedaquiline was the first TB drug to be discovered in more than 40 years, and the first one specifically for multi-drug resistant TB (MDR-TB). MDR-TB arises when the M. tuberculosis bacteria become resistant to two commonly used first-line TB drugs — isonazid and rifampicin.

But less than six months after FDA approved the drug under its accelerated approval programme, is the drug a potential candidate for misuse by doctors in India? Will it in any way result in patients developing drug resistance?

It is too early to say this with any certainty, but the system in India appears to have the perfect conditions to make this possible. The drug is yet to be approved for use in India, and WHO and India have not yet drawn up guidelines to help doctors treat MDR-TB patients with this drug.

But some private doctors here have already started prescribing this drug to their patients by importing it.

Though the Drug Controller General of India is responsible for issuing permits for import, it cannot deny permits to doctors if it is to treat patients.

“Some mechanism should be put in place to regulate the use of this drug,” says Dr. Soumya Swaminathan, Director of the Chennai-based National Institute for Research in Tuberculosis (NIRT). “We cannot have patients developing resistance to this drug as well.”

Already, the prevalence of MDR-TB among new patients is 2-3 per cent. In the case of previously treated patients, the prevalence is 11-17 per cent. Incidence (number of cases detected in a year) of MDR-TB is about 99,000. But these are not a true reflection of MDR-TB incidence/prevalence — MDR-TB patients approaching private doctors are not counted.

“Of this, only a fraction of patients was diagnosed till 2011. From 2012 onwards it started improving,” she says. Between 2,000 and 3,000 MDR-TB patients were put on treatment in 2011. In 2012, around 20,000 MDR-TB patients were put on treatment.

“The drug must be restricted to certain patients to prevent patients developing resistance to bedaquiline,” says Dr. Swaminathan.

Restrictions

She is perfectly right in demanding such restrictions. Janssen Therapeutics, the company that discovered the drug, has underlined this by stating: “reserve [the drug] for use when an effective treatment regimen cannot otherwise be provided.”

WHO, on its part, has made it clear that the drug has to be administered by directly observed treatment (DOT). It has also stated that the “prescribing physician should refer to the national TB treatment guidelines for direction on selection and duration of use of companion drugs.”

The global body has also emphasised that the new drug has to be used “in combination with at least three drugs to which the patient’s isolate has been shown to be susceptible in vitro.” In the absence of in vitro testing results, it should be used in “combination with at least four other drugs to which the patient’s isolate is likely to be susceptible, based on local TB drug resistance data and the patient’s previous TB treatment exposure.”

In all, the recommendations require extraordinary caution by the physicians to make sure that drug resistance does not set in.

Phase III trials

But there is another compelling reason why the drug has to be used with great caution. The drug has been approved based on Phase II trial results. Phase III trial involving more number of people across many countries is set to begin only now.

Mortality

Most importantly, Phase II trial results showed an unexplained increase in mortality in the arm that received the drug. There were nine deaths in the treatment group (79 volunteers) compared with two in the placebo group (81 volunteers). However, five of the deaths in the bedaquiline group and both deaths in the placebo group appeared to be caused by the underlying TB.

Prolongation of the QT interval of ECG (due to changes in the electrical activity of the heart) is an inherent risk of this drug. It can lead to an abnormal and potentially fatal heart rhythm. Hence, a patient has to be monitored very regularly with ECG. Adverse drug reactions connected to the liver (hepatic) were also observed.

The need to be extremely judicious in the way the drug is used cannot be over-emphasised.

Published in The Hindu on May 9, 2013