In a nondescript corner office of the Ministry of Health and Family Welfare (MoHFW) at New Delhi, an official is perched on his seat, frustrated. He is at his wits’ end trying to fulfil demands raised by patients for crucial anti-Tuberculosis (TB) drug Delamanid, primarily used for treatment in kids.

An email by a parent of a 13-year-old kid infected with TB from Telangana, pops up on his computer. The parent is begging for a course of Delamanid to be supplied to his kid. “Almost every other day, parents of hapless patients, mostly children write desperate e-mails to us, seeking for the drug to be made available to them, but the current supply of 400 donated courses is fast running out, and we are not able to fulfil increasing demand,” the official said.

Each course caters to one patient for over a period of six months.

In 2018, Prime Minister Narendra Modi had announced that India will eliminate TB by 2025. Last year, India reported 23.9 lakh TB cases (of which 2.4 lakh - 3.6 lakh are estimated to be children) and, of all reported cases, 66,561 patients were multi-drug resistant, which means that they had stopped responding to the four basic TB drugs and needed tailor-made regimens to which Bedaquiline and/or Delamanid are crucial to add, on a case-by-case basis.

“An additional three lakh patients are still missing, and the national programme has been unable to track them. India recorded 60,000 TB deaths last year, while the World Health Organisation has estimated 4.4 lakh deaths,” said Vikas Sheel, Joint Secretary, MoHFW.

Manufactured by Japanese drug maker Otsuka, Delamanid was approved for restricted use in India in 2017 for patients over six years of age. This means that it is not available on pharmacy shelves for open access to patients, and can only be accessed through a limited pathway.

It was first introduced by MoHFW in September 2018 only to seven states – Punjab, Rajasthan, Karnataka, Odisha, Kerala, Chandigarh and Lakshadweep for patients over six years including adults. On February 5, KS Sachdeva, Head of Central TB Division (CTD) wrote to all States requesting their requirement for Delamanid. The access to Delamanid for age group between 6 to 17 years was expanded to the entire country, and 21 States have been included till date.

“Expanding access meant redistribution of drug courses from the initial seven States to rest of the country based on demands raised,” said the official. United States Agency for International Development (USAID) donated 400 courses of Delamanid to the Indian government, and those stocks have now almost entirely depleted, sources said.

This means that patients have to repeatedly beg and plead with either the government or the non-profits via the Conditional Access Programme, to get access to the drugs.

In an official reply to BusinessLine on February 10, MoHFW confirmed that 364 of the 400 courses have been utilised, of which 292 adults and 72 children have used the drug.

The drug is also used in adults who have exhausted all other options for treatment, and the usage in adults is statistically more because children only constitute of close to 10 to 15 per cent of all TB cases in India. While adults have an option of accessing Bedaquiline, this drug has not yet been approved for children in India by Drug Controller General of India (DCGI), and hence children with drug-resistant TB are left with a sole option of Delamanid for treatment.

“Each of the seven States which were supplied Delamanid, now has less than ten courses of the drug anyway. So these States are rationing their use. Whenever a demand is raised from States where the requirement arises, stocks are re-diverted from States where this drug is available. But this is an ad-hoc mechanism. Such redistribution is becoming increasingly difficult. Any appeal to transfer the drug is being met with refusal. It is a tough situation to be in and shoulder the guilt of a refusal to a wanting kid,” said the official.

India’s quest to purchase Delamanid

One year after sending out a communique that Delamanid will be available across the country, and as the donated courses fast dry out, India is yet to get it's new lot of supplies.

Sources in MoHFW have attributed the delay to incessant negotiations that the Centre was involved in with the pharmaceutical companies – Otsuka and Mylan to bring the drug price down. Delamanid is originally exclusively manufactured by Otsuka in Japan and the US-based Mylan is its distributor in India.

Eight months after seeking replies from States, in the beginning of October, 2019, the Central TB Division calculated the country-wide demand for the drug. In its official reply, MoHFW has stated that this was based on proportion of resistance reported by the laboratories after running solid and liquid Line Probe Assay or culture tests on TB patients.

It calculated the demand of Delamanid to be approximately 1,500 courses, and that for another similarly crucial anti-TB drug Bedaquiline to be 30,000. It later sent a request to the procurement division (CMHS) for purchase of Delamanid. For close to three months then on, the procurement was stuck at negotiation stage with Otsuka and Mylan.

The prices at which the Indian government will buy the drug have now been frozen and purchase orders been placed, sources said. The latest date that MoHFW has pegged for purchased Delamanid doses to arrive in India is now April 2020.

Each course of Delamanid, which lasts six months for a patient, costs approximately $1,700 (₹1,21,577). “The Indian government was locked in negotiations with the pharma companies to bring the prices down. After much to and fro, the companies have agreed to provide every third course for free,” a senior government official confirmed.

The Indian government has raised a request to purchase for 1,384 courses of Delamanid at $1,271 (₹90,643) per course, an up to 25 per cent decrease from original price, derived due to one free course offered on every two courses purchased. This discounted price includes taxes and other overheads, MoHFW said in an official reply. If one third of the courses bought are free, then the Centre spends close to ₹12.54 crore for acquiring the 1,384 courses.

Orders for purchasing the drugs have now been placed, and the government is awaiting the supply of Delamanid from Japan. “It usually takes a few months after placing the orders to receive the drugs. This involves formalities including clearing the customs, which take time. We expect the drugs to arrive by April this year,” the senior government official stated.

Before this, MoHFW has never bought a single course of high-end TB drugs Bedaquiline or Delamanid, all of which have been donated by pharma major Janssen, an arm of US-based Johnson and Johnson and Otsuka, for use in Indian patients.

While Bedaquiline was approved by the US Food and Drug Administration(US FDA) in 2012, approvals for Delamanid came by in 2014. The Drug Controller General of India gave a nod for use of Bedaquiline in 2015 and Delamanid in 2017.

Two years after the nod, India is yet to receive the purchased courses of Delamanid, even as the donated stock is in short supply to meet country-wide needs and has almost run out.

Bring prices down

In an interview with BusinessLine at Hyderabad, Rakesh Bamzai, President and CEO of Mylan Labratories Limited (India Commercial and Emerging Markets), emphasised that Delamanid is a very useful drug for children and TB patients with HIV and diabetes.

“There may be other anti-HIV medication which may have drug interactions with the current available TB medications, while Delamanid works well in that setting. Also for patients with diabetes, Delamanid has less drug to drug interaction with anti-diabetic drugs that are commonly used in managing diabetes,” he said.

While currently Mylan is an exclusive distributor of Delamanid in India, through Otsuka, Mylan is gearing up towards indigenous production of the drug in it’s Bangalore-based facility, and starting supplies in another year or two. However, India will buy it’s first lot of purchased doses from Otsuka’s Japanese unit, Mylan officials said.

Mylan is also hopeful that with indigenous supply picking up, Delamanid prices should come down.

“We will be able to supply the product as manufacturers soon and that will allow us to agree to a lower price with the Government. However, we need to have the new version of the product registered in India and in other countries as well. So we have to take the first step of registration (with the Drug Controller General of India) as it is a variation in the existing dossier even as it is the same product, technology and process. Because the technology is being transferred from Japan to India there is a regulatory process to it. Once the regulators are convinced about the tech transfer as per the regulations they will give us the permission,” said Bamzai.

He further said, “We are currently marketing the product, and production determines the cost. Cost determines the price. At Mylan, we have a desire to see the price come down. Within the next one to two years, Delamanid will be locally manufactured in the Bangalore facility in India by Mylan. This will happen through a technology transfer agreement with Otsuka, in a way that ultimately Mylan will make the Active Pharmaceutical Ingredient. We have recently agreed to supply the first version of the product to South Africa by a tender at a fixed price and the supply will begin next year,” said Bamzai.

He also said, “We are beginning to supply Delamanid now. So it takes any where between six to eight years. It is a typical model that big pharma develops the product, then it gets approved in the US and Europe, and after they do that, they license it to generic companies, get World Health Organization approval and start selling it. That typically takes years.”

But slow uptake, unavailability and shortage of the drug means that while India awaits supplies, patients are slipping through cracks. While the World Health Organization (WHO), in it’s guidelines, has stated that it can be used in kids as young as three, the drug has been approved in India only for patients upwards six years of age.

“The pharma company has to apply to the DCGI for the approvals it needs, age group wise use. Currently the application for approval is in patients, six years and upwards only,” a DCGI official said.

Dr Varinder Singh, Professor, Paediatrics in Lady Hardinge Medical College and Kalawati Saran Children’s Hospital in New Delhi is currently treating a child as young as one year old, for extremely drug-resistant (XXDR) TB. This means that not many drugs work on the child.

The child contracted the deadly manifestation of TB from his mother who died shortly after giving birth to him. “The child was presented to me with XXDR-TB when he was a month old, the youngest patient we have. He is stable on the drug regimens we have designed for him, but he is not cured. We need drugs available for treating younger children like these,” Singh said.

Singh sees at least two to four kids with extremely drug resistant (XDR-TB) or XXDR-TB in the hospital every year and cure rates on current regimens are only 50 per cent. This means that one in every two kids with complicated TB dies. “Because Delamanid is not available, we do not even tell the parents of such an option, and treat kids with alternative drugs,” he further said.

Even for older children, upwards of six years, Singh said, “In Delhi, we have had no access to Delamanid for alternative therapy because access was restricted to seven states of which Delhi was not a part.”

Mumbai-based activist Ganesh Acharya added that Mumbai too, like Delhi had no access to Delamanid under the initially launched pilot programme. “This despite one of the country’s largest Children’s Hospital -- Bai Jerbai Wadia Hospital runs out of Mumbai. Kids in that hospital have been deprived of the drug,” Acharya said.

A 'salvage regimen'

Nestled in the quaint ruins of Mehrauli in South Delhi, is the sprawling campus of government-run National Institute of Tuberculosis Research and Development (NITRD), a stone’s throw away from the 13th century pre-Mughal era structure, ‘Qutub Minar.’ The 1,000-bedded TB hospital is among the top research institutes in the country, and doctors here have lately been dealing with a strange dilemma.

They observed that some TB patients who had already been treated over many years and had developed complicated patterns of drug resistance (DR), which means that a majority of drugs had stopped working on them, could not be put on just one high profile DR-TB drug Bedaquiline alone for further treatment, and that their treatment had to be supplemented with a combination of Bedaquiline and Delamanid. In India, currently, there are no guidelines to administer this combo to patients.

Clinicians however saw no way out. They acquired Delamanid for restricted use through special permissions and in what they call, a ‘salvage regimen,’ and initiated a study wherein they put 53 patients, all aged between 21 to 33 years, on whom most drugs had stopped working, on the Bedaquiline-Delamanid combo over a period of March 2017 to November 2018.

“Each patient received five to ten drugs including Bedaquiline and Delamanid for a minimum period of six months in all patients, and was extended beyond six months in five patients,” the study noted.

Before starting the drugs and during the course of treatment, their eyes were checked thoroughly. Temporary vision loss in some patients, can be a fall out of administering Delamanid. Their electro-cardiogram (ECGs) were recorded regularly, as both Bedaquiline and Delamanid can cause erratic fastening of heartbeat in some patients, which is also referred to as Qtc prolongation in medical terms.

The authors reported that 42 patients had completed the six month intensive phase on Delamanid while the paper was published, while 11 are still on treatment. This study assumes importance because it is the first-ever reported cohort of Indian TB patients to be treated with the Bedaquiline-Delamanid combo.

At the end the paper, the authors concluded that patients showed promising safety profile and sputum culture conversion results at the end of six months on the combo regimen. To understand whether the patient is infection free or not, their sputum samples are subjected to multiple lab tests. Sputum culture conversion in a patient means that the patient’s sputum sample is TB-bacteria free, and that s/he has been cured of the disease.

Authors also maintain that this combination should be extended to patients who have limited treatment options and have failed on a majority of drugs available for TB treatment. They say that this may be the only hope for cure in them, till the time results of clinical trials are made available.

“In such cases there was no option left other than putting them on an individualised treatment option of a salvage regimen containing both Delamanid and Bedaquiline along with other drugs,” Dr Vikram Vohra, co-author of the study and Chief Medical Officer at NITRD told BusinessLine. “The patients received four tablets of Bedaquiline (100 mg each) daily for two weeks, followed by two tablets thrice a week for 24 weeks, whereas Delamanid was given as two tablets (50 mg each) twice a day for 24 weeks,” the study notes.

Of 42 patients, 31 patients are alive and doing well, 10 died during the course of treatment and one patient was lost to follow up. By the end of six months, in 29 patients (94 per cent) sputum smear was negative, which means that there was absence of TB bacteria in their sputum samples, while in two cases, it was not available. Moreover, in 19 of these patients (61 per cent) sputum culture was also negative, while in 10 patients it was not available, while in another two patients the sputum culture test was positive.

Of the ten patients that died, two died during first month of treatment, and had a positive smear and culture at the time of death, which means they were infectious at the time of death while the remaining eight patients died at various points while completion of thirteen months of treatment. “Their last sputum smears and cultures negative at the time of death (which means they were infection-free). Also, the patient who was lost to follow up also had a negative smear and culture,” the paper noted.

“Majority of patients who died were sputum smear and culture negative (indicating absence of in-fectious TB bacteria in sputum) at the time of death. This indicates that transmission risks are re-duced to a considerable extent even from seriously ill patients because of the combo regimen,” the paper concluded.

The paper also noted that only one patient had such high erratic fastening of heartbeat such that drugs had to be discontinued while in others even if there was cardio-toxicity, it was corrected by administering electrolytes, and interruption of drugs within permissible limits for a short span of time or no interruption at all. The doctors concluded that none of the eleven deaths in the study could be attributed to cardio-toxicity which is the side-effect of the drugs to the heart.

Doctors from NITRD, thus emphasise the importance of salvage regimen with access to Bedaquiline-Delamanid combo to save lives. “Preliminary results show that the combination regimen is safe, has high culture conversion rates and tolerated in these patients who otherwise have a low chance of cure and survival. We feel that the data supports safety and tolerability of the combination,” Vohra said.

Doctors have stressed that it is feasible to provide combo treatment under programme conditions and have said that studies should be conducted with larger cohorts.

“However, we also believe that these findings need to be confirmed with a larger cohort and that the patients should be more closely observed with intensive ECG monitoring. Because of varying resistance patterns of the patients, it was not possible to conduct a controlled trial with a larger number of patients,” noted the study.

“The discovery of new drugs Bedaquiline and Delamanid have given some hope and limited reports of effective results are available. Both the drugs exhibit cardio-toxicity (erratic fastening of heartbeat) and WHO has not recommended their combined use in the absence of sufficient evidence. Nevertheless, physicians have been using both the drugs in patients where a WHO-recommended regimen of four effective drugs could not be given without using them and have found to be both efficacious in terms of sputum smear and culture conversion, safe in terms of Qtc prolongation and tolerability,” the paper further noted.

It quoted at least five other international studies, including Tadolini M who in 2016, documented the first case of XDR-TB patient treated with both Bedaquiline and Delamanid in Europe Respiratory Journal. Eventually, Maryandyshev A in 2017 documented that the combo worked in five patients with XDR-TB.

In 2018, Lancet did a retrospective review of 28 patients treated with the combo, since 2016. In 2018, Kim CT et al in European Respiratory Journal said that of 55 patients, with positive sputum cultures at the start of Bedaquiline and/or Delamanid treatment, 39 (70.9 per cent) achieved sputum culture conversion within a median of 119 days.

Unavailability of drug and doctors’ dilemmas

Even after a slew of evidences generated both in India and internationally towards the safety and efficacy of the Bedaquiline-Delamanid combo regimen, the National Treatment Guidelines in India have not been updated to recommend the combo. This is because the Indian government is awaiting the World Health Organisation (WHO) to recommend the combo first, officials in MoHFW said.

Last year, Mumbai-based chest physician Dr Yatin Dholakia identified two of his patients that were in a desperate need for a combo. One was a lady in her forties for whom Dr Dholakia could some-how arrange the combo on time by putting in repeated pleas with Mumbai’s civic body - Brihanmumbai Municipal Corporation (BMC). Another of his patient, an elderly man in his eighties, in September last year, was still awaiting permissions to avail the regimen and was already three months late to access the life saving drugs, especially Delamanid.

“Things are very ad-hoc and we have to be persistent about access. Two of my patients required the combo. One is already on the Delamanid-Bedaquiline combo, and we had to first approach the local district TB officer who then approached the city TB officer and then the state TB officer to get hold of the drugs. The second patient has gone through non-profit route for access but has yet not been started on the regimen. It has been three months since he has been prescribed the regi-men but has yet not been started on the drugs,” Dr Dholakia told BusinessLine in September last year.

Eventually, in the absence of availability of Delamanid, officials in the civic body wrote an e-mail to all clinicians in Mumbai, asking them to stop prescribing patients the salvage combo regimen, because Delamanid was simply not available. The civic body wrote to private physicians saying that they were not in a position to supply the drug and therefore the physicians should stop putting their patients on the ‘off-label use combo treatment.’

“When we ask for providing the combo, Bedaquiline would be started immediately, but for supplying Delamanid, it would take a month or so. This delay is dangerous against the principles of ther-apy. You cannot add one individual drug from a combo regimen that is is lifesaving. If you do this, there is a chance that drug resistance will increase and eventually no drug may work,” said Dholakia.

That Indians are always dependent on WHO guidance to take public health decisions is problematic, comments Dholakia. “WHO has not recommended the combination so far, but there are international reports for use of these drugs, especially from South Africa, and people have done well. Although India is at the forefront of TB epidemic, we and have a lot of experts who have field-level experience, but we always depend on external agencies like WHO. WHO links the guidance to (availability of) funding. Also, have we forgotten our expertise?,” he quips.

Dr Dholakia says, “We are slower, backwards and lagging behind in implementing whatever we need to. Every time we implement something, there is a new challenge staring in our face, which we as a government been able to catch up with.”

Dr Alpa Dalal, another clinician who treats drug resistant TB patients at civic-run Sewri TB Hospital in Mumbai, says that currently she has at least three such patients on Bedaquiline-Delamanid combo. However, she needs access to the combo for many more patients, up to three or four in a month, but putting all of them on treatment is currently impossible.

She rues that there is a spike in the cases who are extensively (XDR) or extremely drug resistant (XXDR) patients and not many options are available to treat them. “When we run Drug Sensitivity Tests on the patient’s samples we realise that the patient is sensitive to only two or three drugs. At times just adding one drug, Bedaquiline is not enough and we need to give them a combination of Bedaquiline, Delamanid and Imipenem. Unless we give them three new drugs there is no chance for these patients to ever be cured, because they have got extensive disease and resistance patterns, so we have to really for-mulate a regimen which could be effective,” Dalal says.

“Then there are some patients who may come back with culture positivity after end-use of Bedaquiline and in such patients too, we need combination. Presently, it seems that the TB programme does not have enough funds for giving this combo,” she further says.

Jennifer Furin, Clinician and Medical Anthropologist at US-based Harvard Medical School comments, “We have been left with no drugs because orders were delayed, does that sound like a country who will eliminate TB in five years? Not to me! Patients that have resistance to the Quinolone drug family need both Bedaquiline and Delamanid, otherwise the chance of their cure is very very low.”

Furin cites an example of South Africa, where all children that need the drug are receiving it. “South Africa constitutes of 50 per cent of Delamanid use globally. How did these two countries (India and South Africa) end up on such divergent paths. It is the honesty and frank discussions of what is not working in South Africa that has led them to improve,” Furin said.

She further said, “It is unfortunate that India introduced Delamanid very late, and gave it to only 400 people. Delamanid is one of our safest drug for children, then why is this drug prioritised to be given in children older than six. Mumbai, where Wadia Hospital is, which is supposed to be the Centre of Excellence for children could not get Delamanid. This is a pity and an embarrassment for India.”

(This reportage was supported by the Thakur Family Foundation. The Thakur Family Foundation has not exercised any editorial control over the contents of this reportage)

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