A widely read blog on intellectual property, SpicyIP, recently published four articles criticising India’s TB programme for dispensing a life saving tuberculosis drug, bedaquiline. The articles – by Prashant Reddy, who teaches law at NALSAR in Hyderabad – were followed by a fifth on the same issue, in NewsLaundry.
This drug could help some of the 1.4 lakh drug resistant TB patients in India, but the articles criticise the Indian government for granting approval to the drug and for beginning the roll out of this drug at all.
What Reddy misses is that TB in India is an emergency situation and patients require urgent interventions, including drugs like bedaquiline.
India currently contributes 25% of all multi-drug resistant TB cases globally. There are at least 1.4 lakh drug resistant TB patients, and this is a conservative estimate. Bedaquiline is prescribed only to drug resistant TB patients who have no other treatment options. Without the drug, their death is nearly inevitable.
In 2013, the World Health Organization issued interim guidelines to countries who need to use this drug. Last year, they reassessed the data and continued to recommend bedaquiline – 63% of patients on bedaquiline were cured, notes WHO.
Notwithstanding this, the thrust of Reddy’s arguments are two-fold.
Firstly, he questions the power of the Indian government to waive local clinical trials for bedaquiline, when phase 3 clinical data is still awaited globally. He argues that such power could not have been exercised and therefore the power has been wrongly exercised.
Secondly, that Janssen (the company which makes the drug) and the Indian government have used India’s Revised National Tuberculosis Control Program (RNTCP) to undertake the work of clinical trials for bedaquiline, without following ethical procedures.
In this article, my focus will be on arguing that Reddy is not correct in questioning the legality of the Indian government’s decision to make this life saving drug available to India’s TB patients at all.
Much of this was already taken on board by the Delhi high court when a young woman from Patna who needed bedaquiline – and was not being given it as the government of India was insisting on giving patients this drug only in five major metro cities – filed a petition. I represented the patient in this case and the high court order gave confidence to the government to increase the roll out of this drug in a phased manner.
A public health emergency
The first thing to consider here is the context: India has 1.4 lakh TB patients who are drug-resistant (DR). That is 25% of the global burden of DR-TB patients. 1.4 lakhs is in fact a partial estimate up to 2016, as India is grossly under-diagnosing TB. These facts are from the recently released “Report of the First National Anti-Tuberculosis Drug Resistance Survey”.
It has taken four decades for bedaquiline to come along as an option for patients with multi-drug resistant (MDR) and extensively drug resistant (XDR) pulmonary TB.
Death is the near certain fate for these patients if they are denied access to drugs, as they have already become resistant to all other treatment options. Therefore, undoubtedly there is a public health emergency which is of concern both to India and the world.
In such a situation should there not be a consensus that the situation needs to be tackled on a war footing?
Can India legally approve this drug?
Reddy argues that the Drug Controller General of India (DCGI) could not have waived a local trial for bedaquiline because “Rule 122 A (read with Schedule Y) of the Drugs and Cosmetics Rules, 1945, mandatorily requires the submission of Phase III clinical data to the DCGI as a precondition for approval.”
This is not true. Nowhere do the rules require that data from Phase III clinical trials be available to the DCGI. They only say that relevant “data is [to be] available from other countries.”
Let us look more closely at Rules 122A and 122B of the Drugs and Cosmetic Act. They provide for approval for import of a new drug and manufacture of a new drug respectively. But in both cases, the law gives an exception for the conduct of local clinical trials. The rules read as follows:
“Provided that the requirement of submitting the results of local clinical trials may not be necessary if the drug is of such a nature that the licensing authority may, in public interest, decide to grant permission on the basis of the data available from other countries.” (emphasis added)
Furthermore, Schedule Y of the Drugs and Cosmetics Act says:
“For drugs indicated in life threatening/serious diseases or diseases of special relevance to the Indian health scenario, the toxicological and clinical data requirements may be abbreviated, deferred or omitted, as deemed appropriate by the Licensing Authority.” (emphasis added)
Several documents from the DGCI clarify in detail what this point means:
“It has been decided that waiver of clinical trial in Indian population for approval of new drugs, which have already been approved outside India, can presently be considered only in cases of national emergency, extreme urgency, and epidemic and for orphan drugs for rare diseases and drugs indicated for conditions/ diseases for which there is no therapy.” (emphasis added)
While approving this drug, the drug controller did in fact take all this into consideration. Their minutes record:
“Bedaquiline is approved in US, EU and other major countries. Bedaquiline is indicated for the treatment of pulmonary tuberculosis due to multi-drug resistant Mycobacterium tuberculosis, (MDR TB) for which presently no effective therapy is available in India. MDR TB is a serious life threatening condition with high mortality and it is a disease of special relevance to Indian Health Scenario.” (emphasis added)
To provide an extreme but current example, the Indian government is currently combatting the Nipah virus by importing drugs which have not even been tested on humans so far.
The situation in India is clearly one of public interest and of an emergent nature, given that there are no other therapies available for MDR/XDR TB patients, where data from other countries can be used. Thus the DCGI rightly exercised its power to waive local clinical trials.
What is the data?
The drug is needed by DR TB patients who suffer from toxicity to injectable agents and resistance to fluoroquinolones. They need this drug as an add on to a regimen with at least five TB medicines. Without access to the drug in their regimens, their death is nearly inevitable as fluoroquinolone resistance is associated with with high rates of treatment failure and death among people with DR-TB.
When the US Food and Drug Administration gave Janssen (a subsidiary of Johnson and Johnson and the holder of the patent on bedaquiline) conditional approval for the drug in 2012, they told the company to return with phase 3 data by 2022. Most DR TB patients today would be dead by the time this comes out. Critics of the drug’s use seem oblivious to these realities.
So far, Janssen has made available data from their phase 2 and 2b trials. Based on this data and even while acknowledging the absence of phase 3 data, WHO still stated the pressing need for bedaquiline. In 2013, they issued their first guideline, recommending use of the drug.
For the 2013 guideline, the WHO constituted an expert group “to assess all available data” on safety, efficacy, tolerability and affordability. This group then recommended the drug to be distributed in controlled environments. This is what India is doing by restricting the drug only to the RNTCP.
Last year, the WHO reaffirmed their recommendation, looking at the data afresh. “New anti-tuberculosis drugs such as bedaquiline represent a major advance in the management of MDR-TB patients. We have gone from having very limited alternatives to treat MDR- and XDR-TB to having now two new drugs which offer hope to patients,” said Dr Mario Raviglione, Director of the WHO Global TB Programme.
Their assessment notes that about two-thirds of patients on bedaquiline were cured by the end of treatment. “Though the risk of undesirable effects could not be entirely explained by current observational data, the guideline development group noted that mortality was not increased in patients receiving bedaquiline, conversely to what was shown in the data assessed in 2013,” they said. Owing to this, they downgraded the undesirable effects of the drug from “large” to “moderate.”
The WHO does not shy away from saying that their decision to issue these recommendations only on the basis of 2b trial data is “a novel step.” This only points to the emergency of this crisis, such that urgent interventions like this are being recognised and recommended, at a global level.
There are currently more than 16,000 persons who have received the drug globally, as of February 2018.
All of this is in fact ‘data’ which the DGCI was entitled to and can use to exercise its powers under Rule 122A or 122B. Therefore the power by the DCGI has been rightly exercised.
Full picture of TB crisis
In the light of this, dithering on providing new drugs to DR TB patients will simply mean that they will die without treatment, even when treatment options now finally exist, with trial data scheduled to be released only by 2022.
If the Central Drugs Standard Control Organisation (CDSCO) had not provided approval for use of the drug in programmatic conditions in 2015 and insisted on local Phase III clinical trials whose data can come out only perhaps by 2022, it would have been disastrous for India’s TB community and indeed, the global TB burden. The pharmaceutical corporation would have been very selective – both in numbers and in criteria – in whom they enrolled and the data would have become available only years later, delaying access for desperately sick MDR and XDR patients.
For an incomparable crisis like tuberculosis, the response will have to be adequately striking. TB is the world’s problem and it is also specifically, India’s problem. India cannot wait around for the world to get its act together, something which could take decades, so that Indian patients can benefit.
In his articles, Reddy raises a second question – asking whether India is running a clinical trial but not giving patients the benefits of being formal clinical trial subjects, by providing them full information and compensation. On this point, I agree with him. The government is obliged to answer the points he has raised. It is shocking that pharmaceutical companies are being hand held by the government and at the same the rights of the persons being administered the drug in respect of consent and compensation are being violated or denied.
However, the drug is still a life-saving option right now. Given the scale of the TB emergency, the fact that the law does not specifically prohibit its distribution in India and the human rights of people who desperately need treatment, it would be wrong to deny bedaquiline to patients who have absolutely run out of all other options.
Reddy correctly notes that a balance must be struck between providing access to treatment for persons whose lives and health are at risk and waiting until there is final phase III data. Lives are to be saved. That should be the primary consideration. But striking this balance means that the bedaquiline should continue to remain approved and rolled out, like South Africa where the MDR TB mortality has been halved. Any course leading to the drug’s withdrawal would be life threatening.
Anand Grover is a Senior Advocate practicing in the Supreme Court of India, Director or the Lawyers Collective and was the UN Special Rapporteur on the Right to Health from 2008 to 2014.