New Delhi: A type of insulin to treat diabetes became the centre of a storm about corruption and other alleged malpractices in India’s regulatory set-up for the pharma industry. However, the case has also raised questions about the rules that govern clinical trials for new drugs.
On 18 August, the Central Bureau of Investigation (CBI) filed its chargesheet against S. Eswara Reddy, a top official in the government’s Central Drugs and Standards Control Organisation (CDSCO) under multiple sections of the Prevention of Corruption Act and conspiracy in connection with Phase III trials for ‘Insulin Aspart’, an injectable drug which the Bengaluru-based pharma company Biocon Biogenics had proposed to import and market in India.
Insulin Aspart already has the approval of drug regulators in the EU and Canada and is widely sold and used there.
The CBI in its FIR, which ThePrint accessed, had further alleged that Reddy “manipulated” the minutes of a meeting about the drug’s Phase III waiver, changing the word “data” to “protocol” so as to cause “wrongful gain” to Biocon. The probe agency has also listed various other accused persons in its FIR, including CDSCO officials and executives from Biocon and other companies.
Biocon, which was founded by entrepreneur Kiran Mazumdar-Shaw, has denied the allegations and emphasised that it “follows due regulatory process for all [its] product approvals”.
While the case will take its own course in the trial court now, the CBI’s action has drawn attention to India’s drug regulatory framework and the relatively recent changes brought to it as part of the government’s initiative to improve and expedite Indians’ access to the latest drugs and pharmaceutical products.
One measure to facilitate this access under Indian rules is a provision to waive Phase III clinical trials for drugs, provided some conditions are satisfied. This provision is used routinely, almost as a regular practice.
Who is eligible for a Phase III trial waiver?
The central issue in the case is the legality of a Phase III clinical trial waiver for Insulin Aspart — a fast-acting insulin that is used to treat patients with diabetes.
Biocon Biologics Limited had sought permission to import and market this insulin injection in India. It also asked for a Phase III trial waiver, citing clinical studies based on which the drug had already received marketing authorisation by the European Medicines Agency (EMA) and Health Canada — the drug regulators for the European Union and Canada respectively. The drug is currently under review by the United States Food and Drug Administration (USFDA).
In India, a Phase III trial waiver is allowed if certain conditions are met under the New Drugs and Clinical Trial Rules, 2019 of the Central Drugs Standard Control Organisation (CDSCO), which operates under the Ministry of Health and Family Welfare.
Under these rules, a Phase III trial can be waived if a new drug has already been “approved and marketed” in countries specified “under rule 101” of the Central Licencing Authority (CLA). These countries include the US, UK, EU, Canada, Australia, and Japan.
The rules further specify that “no major unexpected serious adverse events” should have been reported about the drug in question and there should also be no “probability or evidence” that the medicine could specifically impact the Indian population adversely in any way. The applicant for the waiver must also give “an undertaking in writing to conduct Phase IV clinical trial to establish safety and effectiveness of such new drug as per design approved by the CLA”.
A phase IV clinical trial refers to the collection and analysis of data after a drug has been launched.
Role of a subject expert committee (SEC)
Before granting a waiver, the CDSCO must obtain inputs from a subject expert committee, or SEC, comprising specialists in the therapeutic area the drug is intended.
Waivers for Phase III trials have been granted for the import and marketing of several drugs in the past.
For instance, in May this year, an SEC recommended a Phase III trial waiver for Eli Lilly’s cancer drug Selpercatinib, noting that it was already approved in the US, Canada, Japan, and EU and would meet “an unmet medical need in the country”. The SEC added the proviso that the company should conduct a Phase IV trial in India “for which the protocol should be submitted to CDSCO within two months of approval of the drug for further review by the committee”.
A similar approval was given in July last year for Roche’s Pertuzumab-Trastuzumab injection, with the recommendation that the firm should “submit Phase IV study protocol within 3 months of the approval”.
SEC’s go-ahead for Insulin Aspart — and a controversial ‘correction’
On 18 May this year, Biocon Biologics’ application for a Phase III trial waiver for Insulin Aspart received the go-ahead from a subject expert committee for endocrinology and metabolism, subject to conducting a Phase IV trial in India.
The recommendation from the meeting, which would go on to generate controversy, reads like many other Phase III waiver approvals that came before it:
“The firm presented proposal for import and marketing of the drug with waiver of Phase III clinical trial in the country. The firm presented detailed proposal alongwith CMC [chemistry manufacturing and controls], pre-clinical and clinical trial data.
The committee noted that the firm has conducted Phase I and Phase III trial with the drug in Germany and USA respectively and based on the results of the trial, the drug has been granted marketing authorisation by EMA and Health Canada.
After detailed deliberation, the committee recommended for grant of permission to import and market the drug with waiver of Phase III clinical trial in the country with the condition that firm should conduct Phase IV clinical trial in India (which also includes a sub-set population to generate PK/PD [pharmacokinetics and pharmacodynamics, which refer to how a drug behaves when it is inside the body] and immunogenicity and submit the protocol [emphasis added] to CDSCO before placing the drug in the market) as per existing guidelines in the country.”
One of the CBI’s allegations is that in this recommendation, the word “protocol” (emphasised in text above) replaced the word “data”.
“Dr. S. Eswara Reddy, JDC has manipulated the Minutes of the Meeting of SEC held on 18.05.2022 by changing the word “Data” to “Protocol” in the recommendations and thereby causing substantial wrongful gain to M/s Biocon Biologics Limited, Bangalore,” the FIR, which ThePrint has accessed, says.
However, industry experts indicate that the correct word in this context is indeed “protocol”, and not “data”.
‘Protocol’ vs ‘data’
Sometimes also referred to as “post-marketing surveillance”, Phase IV trials generate vast volumes of data as a new drug is used in patients of different age groups and health profiles. This is an important stage in drug development because, as a paper in the journal Perspectives in Clinical Research points out, it produces data about the “real-world effectiveness” and safety of a medicine.
Pharmaceutical industry sources told ThePrint that since the recommendation is to allow marketing of the drug with the proviso that a Phase IV trial should be carried out, there is no way to submit data in advance of a drug actually being used by patients.
The word “protocol”, on the other hand, refers to the procedure, method, or design of data collection. The earlier mentioned CDSCO rules also reference this in the clause about Phase IV, stating that these clinical trials to establish safety and effectiveness of a new drug must be conducted “as per design approved by the CLA.” No mention is made of “data”.
Speaking to ThePrint, an industry source clarified that a Phase IV trial can be done only after a product is launched.
“The Phase IV data cannot be presented prior to going to market… Thus, to be factually correct, the word ‘data’ may have been replaced with ‘protocol’ in relation to the Phase IV study recommended by the SEC. Hence, this substitution of the word was not done to benefit Biocon, but was just a factual correction to be in line with the regulation,” this source said.
The ‘corruption’ allegations
According to a statement released by the CBI in June, CDSCO joint controller S. Eswara Reddy was ‘caught’ while accepting Rs 4 lakh as part of a Rs 9 lakh payment to “favour Biocon” and waive the Phase III clinical trial for the Insulin Aspart injection.
The CBI has also alleged that it had received “reliable information” that Guljit Sethi alias Guljit Chaudhary, the director of a company called Bioinnovat Research Services, was handling government regulatory work for Biocon and was acting as a “conduit” to deliver the payment “for processing the files favourably” through Dinesh Dua, the director of a firm named Synergy Network India.
Dua and Sethi were also arrested, as were Biocon Biologics associate vice-president L Praveen Kumar and CDSCO Assistant Drug Inspector Animesh Kumar.
“Sethi …has conspired with L Praveen Kumar, Associate Vice President and Head — National Regulatory Affairs (NRA) and other senior executives of M/s Biocon Biologics Limited, Bangalore to pay a total bribe amount of Rs 9 lakh to Dr S Eswara Reddy for favourably processing the said three files related to M/s Biocon Biologics Limited, Bangalore and also for favourably recommending the file of ‘Insulin Aspart Injection’ to the Subject Expert Committee (SEC) meeting on 18.05.2022, and had supported for waiver of Phase Ill clinical trial for the Insulin Aspart Injection drug of Mis Biocon Biologics Limited, Bangalore,” the FIR said.
ThePrint e-mailed the CBI with specific questions about the alleged irregularities committed. This article will be updated when a response is received.
In a statement issued on 21 June, Biocon denied the allegations. The company said: “All our product approvals are backed by science and clinical data. Our biosimilar Insulin Aspart has undergone full global clinical trials and is approved by global regulatory agencies like EMA and Health Canada.”
It added that the rationale for seeking a waiver of Phase III clinical trials for Insulin Aspart in India, “was based on the following Indian regulatory guidance: Similar Biologics Guidelines 2016 & New Drugs and Clinical Trials 2019…”
The company further stated that “the entire application process in India is online and all meeting minutes can be found on the website of the Central Drugs Standard Control Organisation.”
Disclosure: Kiran Mazumdar-Shaw is among the distinguished founder-investors of ThePrint. You can see the full list here.
(Edited by Asavari Singh)