Drug Regulation

Special Report: The Smoke & Mirrors Surrounding the Approval of Bedaquiline


Co-authored with Balaji Subramanian, 5th year student, NALSAR University of Law

Prologue

Bedaquiline

Last Sunday, The Hindu ran a piece on its front page alleging that  the government was not even considering the option of issuing compulsory licenses for a newly patented drug called bedaquiline, despite access to the drug being restricted to less than 1,000 patients. Bedaquiline, which is currently the most promising drug candidate to treat multi-drug resistant tuberculosis (MDR-TB) was developed and patented by Janssen and The Hindu claims that the company is only donating a few hundred doses of the drug when, in fact, thousands of Indians need the drug. The report further claims that Janssen is not willing to issue voluntary licences to Indian manufacturers and since access to the drug is being curtailed, the government should step in to issue a compulsory license. In other words, The Hindu report creates the impression that patents are once again the problem. 

Co-incidentally, we have been researching this issue for a few months now and can confirm that access to bedaquiline has been curtailed because Phase III trials with the drug are yet to conclude. The Hindu’s story has completely missed this core issue.

What follows is our analysis of the bedaquiline question. This isn’t about Big Pharma refusing to license a new drug – it’s much more insidious. It is about the government ignoring the law to grant marketing approval to a drug without mandatory Phase III clinical trials and then subsequently carrying out a de facto clinical trial on approximately 800 Indian patients at 6 government hospitals with doses that have been “donated” to it by Janssen and the United States Agency for International Development (USAID). In return for these donations, we speculate that Janssen is going to get valuable clinical data from the Indian government. The worst aspect of these de facto clinical trials is that the “informed consent” form that patients are required to sign to be enrolled for treatment includes a clause forcing them to give up any possible claims for compensation for any adverse effects caused by bedaquiline.

I

Background

In January 2017, the media reported on a first-of-its-kind legal dispute in India where a young woman residing in Patna, suffering from multi-drug resistant tuberculosis (MDR-TB), sued the Ministry of Health and a government hospital demanding access to a potentially life-saving drug called bedaquiline.

Developed and patented by Janssen, bedaquiline is the first new drug to receive approval to treat tuberculosis (TB) in over 40 years. It is potentially the only drug left to treat MDR-TB, which is a form of TB that is resistant to all first-line drugs. India reportedly has 79,000 patients suffering from this form of TB. The woman, who was a resident of Patna, was reportedly denied access because she didn’t meet the domicile requirement imposed by the government as a precondition to access bedaquiline.  At the time of the litigation, the government gave multiple reasons for restricting access to this drug to a mere 6 government-run hospitals in the entire country. The sworn affidavit (obtained by us under the RTI Act, available here) filed by the Ministry of Health before the Delhi High Court justified the restrictions on the ground that the drug was associated with adverse reactions on the cardiac rhythm of patients studied in a clinical trial, thus requiring close monitoring of all patients who were prescribed it. Separately, in a statement to the Wall Street Journal, the government’s lawyer justified the restriction on the ground that the government wanted to minimize the risk of patients developing resistance to the drug. In any case, the high-decibel media campaign that accompanied the case ensured a quick resolution – the government entered a consent decree with the woman’s father that would allow her to access the drug through a private doctor in Mumbai.

Whether a domicile rule actually existed at the time is not clear, but the reportage gave the impression that the court judgement opened the door to a larger number of India’s 79,000 MDR-TB patients being able to access the drug. Curious about the actual number of patients being allowed access to the drug, we filed an RTI application with the government asking them for the number of patients who were being treated with the drug. In its response, the Ministry informed us that as of October 31, 2017, more than 9 months after the High Court’s order (and 24 months after the drug was approved by the DCGI), only 824 patients had been treated with this drug through the Conditional Access Programme (CAP). Of these, 152 were from Gujarat, 199 from Tamil Nadu, 149 from Maharashtra, 353 from Delhi and 51 from Assam. We also checked the “statements of working” filed by Janssen under Section 146 of the Patents Act, 1970, which requires all patentees to disclose the extent to which the invention has been sold or worked in India. For the year 2015, when the drug was first approved for treatment, the patentee claimed no sales, whereas for 2016, it claimed to have donated 300 units free of charge to the government (but recorded no commercial sales).

In other words, only 1.04% of the total 79,000 Indian patients afflicted by MDR-TB have received the drug.

II

How was bedaquiline approved in India without Phase III clinical trials?

Unable to comprehend the startling low access rates to bedaquiline, we decided to dig deeper to understand why exactly the government wasn’t making the drug available to more people. Was it because the government was simply dragging its feet, as alleged by activists, or was there some other reason? Legally speaking, a drug approved by the Drug Controller General of India (DCGI) can be accessed by anybody subject to certain safeguards such as the requirement of a medical prescription for certain scheduled drugs. We asked Ministry of Health to provide us the legal basis for restricting access to the drug through a CAP that made it available only through a small number of government hospitals and no private hospitals, although the latter could source the drug directly from Janssen under a compassionate use program. The Ministry’s answer was surprising because it justified the access limitation “as the safety profile of the drug has not yet been established through the Phase 3 clinical trials”. A similar statement was made by the Ministry in its affidavit before court – that the drug had not gone through Phase III clinical trials. Across the world, the approval process for a new drug is hinged on a three-step clinical trial program. Phase I trials are conducted on a small number of patients to gauge safety and tolerability. Phase II trials are exploratory trials to judge the efficacy of the drug on a small number of patients suffering from the disease in question. Drugs that show promise of treatment are taken to the next stage. Phase III clinical trials are of crucial importance, since they are conducted on a large cross-section of patients actually suffering from the disease in question. The data generated in such trials is crucial to establish the drug’s safety and therapeutic efficacy, and many drug candidates which pass the first two stages, fail at this stage of testing. Without Phase III trials, doctors do not have enough data to scale up treatment to all patients.

The Ministry’s claim that the drug had not gone through Phase III trials is worrying 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. How, then, did the DCGI approve this drug when no Phase III clinical trials were conducted?

To answer this question, we had a look at the minutes of the Technical Committee on clinical trials. This is a committee set up pursuant to public interest litigation before the Supreme Court and has no statutory recognition. However, the DCGI, which is the statutory authority responsible for approvals, usually concurs with the Committee’s recommendations. The minutes of the Technical Committee (headed at the time by Dr. Jagdish Prasad Director General of Health Service (DGHS) from December, 2014 record that the Subject Expert Committee (SEC), which consists of experts in the field for which the drug is being considered, had initially denied a request to waive the conduct of Phase III clinical trials in India on the ground that only 5 Indian patients were enrolled as a part of an earlier global clinical trial of bedaquiline. Subsequently, the minutes record that the DGHS convened a meeting attended by the TB Division of the Health Ministry, and representatives of Janssen. At this meeting, it was decided to recommend that the DCGI approve the drug, but limit its distribution through a CAP.

The Technical Committee then reviewed the decision of the SEC and made two important observations. First, it noted that “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, (MDRTB) for which presently no effective therapy is available in India.” Second, it approved the waiver of local clinical trials and recommended that the drug be made available only through a CAP.

The reasoning provided by the Technical Committee is incorrect in both fact and law. To begin with, the approvals in the US and EU were anything but ordinary.  Under American law, there is a specific framework to grant accelerated approval for drugs that show promise during trials on the basis of a surrogate endpoint. For example, if a drug has the effect of visibly shrinking the size of a cancerous tumour, the USFDA may grant accelerated approval in order to benefit patients. Such accelerated approval by the USFDA allows more patients to access the drug but still requires the manufacturer to continue generating safety and efficacy data through Phase III clinical trials for a traditional approval. Bedaquiline was approved in the United States under this framework because there was evidence of sputum conversion, which is a reasonable predictor of the drug’s efficacy against TB. However, there were other issues pointed out by the USFDA such as high mortality during Phase II trials. The causation for these deaths wasn’t yet clear and Janssen was under an obligation to carry out further trials. The accelerated approval letter from the USFDA to Janssen clearly placed the company under an obligation to carry out a confirmatory Phase III clinical trial. The emphasis on Phase III trials stems from numerous instances of drugs showing promise in Phase II trials but failing in subsequent, more rigorous Phase III trials. The letter also mentions that bedaquiline will be subject to all the other conditions that form a part of accelerated approvals. The EU also only gave conditional approval to the drug, subject to an annual review.

Indian law does not have the equivalent of “accelerated drug approval” (at least until the Draft New Drugs and Clinical Trials Rules 2018 are notified) and no marketing approval can be given without conducting Phase III clinical trials. At most, Rule 122A, allows the DCGI to waive “local clinical trials”. The local clinical trials requirement exists in India as a means of forcing pharmaceutical companies to generate data on the efficacy of a drug on the Indian population because most Phase III trials are conducted in the West, and it is possible that a drug works on Indian patients differently owing to differences in race, genetics, diet, etc. The law allows for the waiver of these local clinical trials in case there is already substantial, broad-based Phase III data from clinical trials abroad. The actual manner in which these exemptions are granted has been the subject of criticism from the Parliamentary Standing Committee on Health. The point to be stressed is that although the DCGI has the power to waive local clinical trials, the law does not allow him to waive the requirement of Phase III trials altogether – there must be data from Phase III trials conducted somewhere in the world. However, from the affidavit and RTI reply of the Ministry of Health, it is clear that Bedaquiline has not gone through any Phase III trials, anywhere. This is a very significant point because apart from the illegality of the approval itself, it raises serious ethical questions about the treatment being provided at the 6 government hospitals.

III

Is the government carrying out de facto clinical trials on behalf of Janssen? 

The simple question that should be asked of the Ministry of Health is whether the treatment being offered at those 6 hospitals are de facto clinical trials. The guidelines under which the government has been administering bedaquiline reveal that, for all practical purposes, the 6 government hospitals have been running a clinical trial. All patients are required to sign an “informed consent” form prior to treatment and are closely monitored because the government is aware of potential adverse events. The patients are also being told that their clinical status will be shared with “relevant authorities”. However, the DCGI’s approval of bedaquiline (a copy of which we obtained, available here) is conditioned on Janssen conducting a post-marketing surveillance study and submitting the said data to the DCGI. Therefore, it is clear that the government hospitals must turn over the clinical data to the manufacturer. Yet, the informed consent form does not mention this possibility of data being shared with private parties. This is a serious ethical breach.

Why, then, isn’t the government classifying the treatment at these 6 hospitals as a clinical trial? If it had, the government hospitals would have been required to seek approval for a clinical trial under Schedule Y to the Drugs & Cosmetics Rules, 1945. This would have entailed the vetting of the entire treatment protocol by external experts on various scientific and ethical parameters, to mitigate potential conflicts of interest. The trial would have been constantly monitored by external experts and accountability for adherence to ethical protocols during the trial would have been fixed with specific doctors. Most importantly, patients would have been entitled to compensation in case they faced adverse effects due to the drug.

Instead of following the above safeguards mandated under the law, we have the government forcing patients to sign an “informed consent” form that has the following condition: “I understand that I am not eligible for any compensation in case of any adverse effect under this programme”. Why should patients being administered an experimental drug be forced to waive their legal rights?  Appendix XII to Schedule Y of the Drugs & Cosmetics Rules, 1945, which was inserted into the law in 2013, provides clinical trial subjects and their relatives the right to compensation. What now happens to patients if their condition worsens because of the drug? Are they to suffer the consequences on their own without any aid from either Janssen or the government?

Another problem with the “informed consent” form is that it does not give patients all known information about bedaquiline. One of the other conditions states: “I have been informed that there are known side effects that may cause discomfort to me and possible unknown side effects of the new drug Bedaquiline.” The American regulator, however, requires Janssen to carry the following black box warning: “An increased risk of death was seen in the SIRTURO treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial”. There is no mention of this crucial information on the informed consent form that Indian patients are required to sign to access bedaquiline. The accompanying patient information booklet only tells patients that possible side-effects include palpitations and changes in heart rhythm. Similarly, the Janssen label approved by the USFDA is required to inform patients that the drug has gone through only Phase 2 trials and that that “The safety and efficacy of [bedaquiline] for the treatment of […] tuberculosis has not been established”. This information is not available on either the informed consent form that Indian patients sign, or in the patient booklet, which only informs patients that the drug has shown “promise” in earlier trials.

IV

Is the Government of India giving away clinical trial data to Janssen?

There have been reports in the media that Janssen is donating Bedaquiline to the Indian government through the US Agency for International Development (USAID), an arm of the US Government. This move by Janssen insulates the company from any liability for anything that goes wrong during the government of India’s clinical trials. The more important question that we must pose at this stage is regarding the terms of this agreement. We filed an RTI application with the Director General of Health Services (DGHS) asking for a copy of all “all communications between the Ministry of Health and Janssen & Janssen regarding the purchase, donation, use etc. of bedaquiline.”  The application, which also contained other questions, was transferred to the Central Drug Standard Control Organisation (CDSCO) which gave us a one-line reply claiming the answers to all our questions were available online. We could not find this information online.

The reason we requested the government for this information was because we wanted to understand the nature of data that would be shared by the government with Janssen. That the government must share the data from its clinical trials with Janssen is a foregone conclusion because the DCGI’s approval is contingent on Janssen submitting post marketing data to the DCGI. It is very likely that Janssen requires, in exchange for donating the drugs to India, information on how exactly the drug is performing on Indian patients, who are eventually going to be the largest market for the drug.

While sharing data with Jansen isn’t objectionable (provided patient confidentiality is protected and informed consent is taken), we do hope that the government negotiated a good deal with Janssen for access to all the clinical data that it is able to generate through other trials on the 800 odd patients currently being treated at the 6 hospitals. We stress on this aspect because the government of India is currently bearing both the cost of administering the drug, and the risk of adverse events on those 800 odd patients being treated with bedaquiline. If the Indian taxpayer is underwriting the riskiest and most expensive stage of a clinical trial, it follows that the Indian taxpayer should get a substantial discount in final price of Bedaquiline once Janssen decides to start profiting from the sale of the drug. After all, India offers the best sample patient group for MDR-TB and the data from India will be crucial to establishing the efficacy of Janssen’s drug.

Before we conclude, we would like to caution readers that we are in no way commenting on the efficacy of Bedaquiline – that is not an area of our expertise. At the same time, we think Indian journalists needs to dial back their enthusiasm about Bedaquiline because there are several drugs whose performance in Phase III trials disappoints predictions made from Phase II results. A case in point, is the clinical experience with Delaminid, the second TB drug mentioned in The Hindu report that we referred to in the beginning of this piece. Although this drug showed promised after Phase II trials, recent Phase III trials were disappointing. In fact, it was The Hindu that reported on this aspect just two months ago in January, 2018. Sunday’s report in The Hindu was silent on this issue.

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Prashant Reddy

Prashant Reddy

T. Prashant Reddy graduated from the National Law School of India University, Bangalore, with a B.A.LLB (Hons.) degree in 2008. He later graduated with a LLM degree (Law, Science & Technology) from the Stanford Law School in 2013. Prashant has worked with law firms in Delhi and in academia in India and Singapore. He is also co-author of the book Create, Copy, Disrupt: India's Intellectual Property Dilemmas (OUP). He has recently been appointed as an Assistant Professor at NALSAR, Hyderabad, starting September 1, 2017.

2 comments.

  1. Anonymous

    Prashant – I think you nearly nailed it. Well researched. Should be an eye-opener for many who claim to be experts in the field.

    Reply

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