Drug Regulation

RTI Replies Reveal the Deal between Janssen and the Ministry of Health on Bedaquiline


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

Bedaquiline

Subsequent to our previous post, we got a copy of some of the correspondence between Janssen and the Ministry of Health under the RTI Act. We were under the impression that our request for the information was transferred to the CDSCO which then disposed the application without giving us the requisite information. However, it appears that the application was transferred back to the Central TB Division, which processed the request and sent us the information yesterday. We don’t think we have been provided with the entire chain of communication between the Ministry and Janssen, but it still helps fill in a few of the blanks.

The Conditional Access Programme for bedaquiline was Janssen’s idea

The most important letter is the one dated May 28th, 2014 from Sanjiv Navangul, Managing Director, Janssen India to Dr. Jagdish Prasad, the Director General of Health Services (DGHS), Ministry of Health and Family Welfare. (Dr. Prasad has been in the news recently because of a suspension order due to a vigilance inquiry. The status of his employment with the Ministry is not clear as of now.)

In this letter, Janssen’s Managing Director informs the DGHS that his company had requested the New Drug Advisory Committee (NDAC) on 28th February, 2014 for a waiver of phase III clinical trials for bedaquiline in order to allow early access for Indian patients. The NDAC, consisting of subject matter experts, rejected the request since Janssen had conducted only a Phase IIb study, and only 5 Indian patients were part of this trial. As Janssen acknowledges in the letter, the “NDAC felt that the number of subjects from India was not adequate to address the safety concern and hence did not agree for the waiver of Phase III clinical trial”. The recommendation of the NDAC can be read over here. This Committee, consisting of specialists, had noted that Jansen has “requested for the waiver of requirement of phase-III clinical trial in India” since it had conducted only “Phase IIb study”. This request was rejected by the Committee on the grounds that “The number of subject from India was not considered adequate to address the safety concern. The committee therefore does not recommend for the waiver of clinical trial.”

In his letter to the DGHS, Janssen’s MD explains the advantage of waiving Phase III clinical trial “We believe that this step [the NDAC decision] would result in a considerable delay for the drug to reach patients suffering from MDR-TB in India, thereby denying them a viable new treatment option. The drug is authorized for the treatment of MDT-TB in 30 countries in the world which includes geographies of Asia, the United States of America, and Europe.” Apparently concerned by the burden of MDR-TB in India, the company applied for reconsideration to the DCGI (which is the final authority on drug approvals) because according to it, if India were to wait until Janssen completed Phase III trials, it would have to wait until 2021. The company also informs the Ministry of Health that even if it were to undertake an India-specific phase III study, access to bedaquiline by Indian patients would still be deferred by at least 4 years.

Janssen then proposes a third option, on the lines of what they had adopted in the EU. In pertinent part, the letter states, “We propose a structured risk management plan to minimize inappropriate use of Bedaquiline”. This plan had three elements:

“a. Controlled distribution and prescription exclusively through RNTCP framework;

  1. Enhanced passive surveillance (supported by Janssen, to be implemented in consultation and collaboration with RNTCP);
  2. Bedaquiline Registry (supported by Janssen to be implemented in consultation and collaboration with RNTCP)”

The letter can be accessed here.

The government’s subsequent action reveals that the DGHS followed Janssen’s recommendation. The Technical Committee, on December 19, 2014, noted that the minutes of an earlier meeting convened by Dr. Jagdish Prasad recommended the waiver of phase III clinical trials and allow access through only the RNCTP framework for conditional access, and accepted this recommendation. This decision was then approved by the Apex Committee headed by the Health Secretary on December 24, 2014. (These committees were created in an ad hoc manner after the Supreme Court came down hard on the government for irregularities in the conduct of clinical trials).

The committees appear to have been swayed by the fact that Bedaquiline was approved in the US, EU and other major countries and that there was no effective treatment for MDR-TB. As we explain in the previous post, the approvals in the US and EU were conditional, and different from regular approvals after Phase III trials in that they are subject to conditions such as labelling on the drug to inform patients of the unverified safety and efficacy of the drug. As we also explained in our earlier post, Rule 122A of the Drugs & Cosmetics Rules, 1945 only allows for the waiver of local clinical trials in India not global phase 3 trials – in fact, at the particular meeting where bedaquiline was approved, the Committee was considering mostly requests for waivers of local clinical trials not global Phase III trials. The question now is whether the Committee made a mistake i.e. did they confuse the approvals granted in the US and EU for regular approvals without noting the difference between conditional and regular approvals? Or did they simply decide to ignore the mandate of Rule 122A? Either situation is deeply worrying.

The government’s options if it had followed the law under Rule 122A

If the government had rejected the request for waiver of Phase III trials, it had two other options. The first option was to ask Janssen to sponsor a Phase III trial in India. If Janssen was reluctant to do so because of the regulatory nightmare surrounding clinical trials in India, the government could have sponsored the clinical trial with public money and shared the data with Janssen subject to Janssen agreeing to substantially lowering its price for the drug. Instead, the government waived phase 3 trials and started treatment under a conditional access program which looks a whole lot like a Phase III clinical trial. The problem with this approach, like we mentioned earlier, is that the patients under the CAP don’t get the same rights assured to clinical subjects who are enrolled in a registered clinical trial. The trial sponsor would have had to pay compensation in case there were adverse effects of the drug. The government has, however, forced patients to give up any claims to compensation. Also, the clinical trial would have been conducted with safeguards such as oversight by an Ethics Committee, external approval of the treatment plan, etc. These safeguards exist in the law for a reason – to protect patients from over-ambitious doctors looking to build their reputations and calculating pharmaceutical companies, whose commercial interests may conflict with those of vulnerable patients. Such ethical concerns cannot simply be brushed aside. Over the last few days, we have seen many Indian journalists trivialize the importance of Phase III trials in establishing the safety and efficacy of a drug without understanding that this is the law of the land. It cannot be ignored.

But let us return to the approval process. After the Apex Committee’s meeting, the Drug Controller General of India (DCGI) approved the drug on January 14, 2015 for the following indication “In adults (> 18 years), as part of combination therapy of pulmonary tuberculosis due to multi drug resistant Mycobacterium tuberculosis when an effective treatment regimen cannot otherwise be provided”. The two other conditions imposed by the DCGI was that the drug would be made available only through the government run “Revised National Tuberculosis Control Program (RNTCP) framework for conditional access” and that Janssen would be required to conduct a post marketing surveillance study of the drug and submit the necessary information to the DCGI. Unlike its counterpart in the US, the DCGI did not require Janssen to inform patients that the safety and efficacy of the drug was yet to be conclusively established. A copy of the approval can be accessed here.

The Expert Committee on Regulation of Newer Anti-TB drugs

One February 4, 2013 the Central TB Division of the Ministry of Health had reportedly set up an Expert Committee on “Regulation of newer TB drugs in India”. We haven’t been able to find much information on this committee in the public domain. The only references are in a MSF submission and a parliamentary question from 2016. Surprisingly we are not even able to find a list of members on the committee.

On July 24, 2014 it appears that the committee headed by the DGHS held a meeting with Janssen on the issue of “Regulation of Newer Anti-TB drugs” to discuss the regulatory way forward for bedaquiline. A Janssen representative references this meeting in a letter dated August 11, 2014 where he summarizes the data provided to the government. Some interesting information includes the fact that in one of the phase II studies (C208), bedaquiline demonstrated a 26% absolute increase in cure rates and reduced the time of sputum conversion by 42 days. The letter also sought to explain the high number of deaths of patients in the bedaquiline trials by attributing them to a number of other factors not related to bedaquiline. This includes alcohol poisoning, hepatitis, septic shock, cerebrovascular accidence, motor vehicle accident, lung infection, etc. etc. The letter however provides no citations to independent sources confirming the same. The letter also clearly states that “[a]s part of commitment to regulatory authorities in US and EU, Janssen is planning to conduct a large global phase III program, to further evaluate efficacy and safety of Bedaquiline.” Simply put, Phase III trials are important and cannot be trivialized. This letter can be accessed here.

On October 17, 2014 the DGHS, on the advice of the Expert Committee, directed that bedaquiline be approved for CAP under RNTCP. We don’t have copy of the approval letter but this regulatory event is referenced in one of Jansen’s letters.

The Data Sharing Agreement between Janssen and the Government

Four months after the DCGI’s approval, on April 21, 2015, a Janssen representative wrote to the Deputy Director General of the Central TB Division. The letter (available here) explains that since bedaquiline is being administered through the RNTCP and Janssen is obligated under the law to provide post marketing data to the DCGI, the government would have to give the company access to all clinical data generated by the 6 government hospitals running the Conditional Access Program (CAP). The company makes it clear that “it is not feasible on part of J&J to conduct a separate post marketing surveillance study along with active monitoring”. In order to facilitate the sharing of information, J&J proposed that both parties sign a “Data Sharing Agreement”. A copy of the agreement, which requires sharing of non-identifiable patient data (i.e. anonymized data) has been provided to us and although it is signed by Janssen’s representative, we are not sure whether the government actually signed the agreement. A copy of the agreement can be accessed here.

This agreement requires RNTCP to mandatorily share all information pertaining to Adverse Drug Reaction, Adverse Event and Serious Adverse Events within 24 hours of its occurrence. A separate clause requires “regular” sharing of data, wherein information was required to be shared at regular 6 month intervals in a consolidated form and a final report on conclusion of the CAP. The agreement also requires the government to grant Janssen a “non-exclusive licence to use such non-identifiable patient data for the Agreed Purpose”. We were unable to find the definition of the phrase “agreed purpose” anywhere in the agreement but we speculate that this means that Janssen can use this data commercially in the sense that it can use this data to secure final regulatory approvals. In other words, Janssen gets to use this clinical data generated on 800 Indian patients for getting final regulatory approval. If the government has given away this valuable data without seeking enforceable commitments from Janssen on the price of bedaquiline in the future, then heads must roll in the Ministry of Health. The risk and cost of running this conditional access program is enormous and it is the Indian exchequer that is bearing the risk, not Janssen.

The rest of the correspondence is mainly on the modalities of transferring the drugs to the 6 government hospitals – you can download all documents in a consolidated format from this link. We must caution readers that we do not know if this is the entire chain of correspondence. It is possible that some documents have not been given to us.

The Hindu’s reporting on the issue

Before we end, we must point out an issue with The Hindu’s second recent report on the issues surrounding bedaquiline published on Monday. After the publication of its first report, Arun Jha, a Health Ministry official had tweeted the following, explaining the reason for the government curtailing access to bedaquiline: “Bedaquiline & delamanid are Cardiotoxic & side effects associated need to be strictly monitored. SANS phase 3 trials, regulatory authority only permitted conditional access. As per WHO recommendation all Drug resistant patients don’t need new drugs which are cardiotoxic.” This is basically the same reason that we explained in our earlier post. The print issue of The Hindu however misinterprets Mr. Jha’s tweet by paraphrasing it in the following manner: “Arun Jha, Economic Advisor to the Health Ministry, said on Twitter, that tighter control of new drugs is necessary to ensure patients do not become resistant to the newer therapies.” This is a misinterpretation of the tweet because Mr. Jha’s tweet (As reproduced only in the digital edition of The Hindu and not in the print issue) does not make any reference to increased resistance – his concern is increased mortality which is a valid concern. The concern with increased resistance has been cited by some officers as the cause for curbing access to the drug but is not the actual reason for curbing access to the drug.

Either unaware or misinformed of the nature of Mr. Jha’s tweet, Harvard medical Professor  Jennifer Furin is then quoted in the same Hindu report slamming Indian medical officials with the following comments, “Patients seeking treatment for MDR-TB are not offered these drugs, with public health officials priding themselves on “saving” the drugs. Imagine if you were a person living with MDR-TB, and there is a drug that can increase your chance of cure but your physician tells you that you cannot have it because there are some un-named, un-identified populations who might ‘need it in the future.’ That is, essentially, what happens hundreds of times a day in India when doctors turn away DR TB patients who need the medicines,”.

Dr. Furin has clearly been misinformed – the government’s reason for curbing access is not because it is “saving” the drug for future uses. As explained by Mr. Jha in his tweet and by the Ministry in its sworn affidavit to the Delhi High Court, there is not enough clinical data to substantiate the safety and efficacy of the drug since Phase III clinical trials have not yet been concluded.

We would caution journalists covering this story to remember that there is a line between activism and journalism.

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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.

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