A few weeks ago, the Indian pharmaceutical company Intas voluntarily “curtailed the distribution” of Razumab, a biosimilar drug used for treating macular degeneration, following reports that it caused severe inflammation of the eyes. The recall, coming barely two months after the drug’s launch, didn’t raise many eyebrows. Nor did it prompt any debate. It really should have.
While it’s appreciable that Indian companies are finally stepping up to their ethical and legal duty of withdrawing unsafe medicine, the episode raises serious questions about the competence of India’s regulatory regime for biosimilar drugs or biosimilars.
What are biosimilars?
For most of the last century, new drugs developed by the pharma industry were based on engineering chemical entities. These were relatively easy to reverse-engineer, giving us the whole industry of generic drugs. And for generic drugs to get marketing approval, they had to clear simple tests to prove their “equivalence” to their original, or “innovator”, counterparts.
Change set in during the 1980s when a breakthrough in the science of gene-splicing sparked off the biotech revolution in the US. For the first time, scientists could manipulate and modify genes to achieve stunning results. They could manufacture human insulin, create genetically modified crops, and ultimately build an entire new class of drugs called biologics.
The science of biologics is completely different from that of conventional chemical drugs. As Fortune magazine describes, biologics “are made using living cells that treat disease, usually by genetically modifying cells. They are big and very complex molecules, often 200 to 1,000 times the size of more common small-molecule drugs”. To explain with an example: aspirin, a small-molecule drug, is made of up 21 atoms, whereas the biologic drug Enbrel, which treats rheumatoid arthritis and plaque psoriasis, is made up of over 20,000 atoms.
As a result of this complexity, manufacturing a biologic is a challenging affair: even a small change in the manufacturing process can cause big changes in the drug’s efficacy. Equally difficult is the process of making an equivalent drug: companies have to find their own way to engineer living cells to provide the same results as the original. These imitations, called biosimilars, are relatively less expensive than the original biologics.
Given all this complexity, it has been necessary worldwide to create a whole new regulatory framework for authorising biosimilars. The kind of simple and limited clinical studies needed for chemical drugs simply don’t work for biological molecules. That is why the global standard for approving biosimilars has been to establish both safety and efficacy independently, because biosimilars are fundamentally different from biologics.
Did the industry drive the agenda?
In India, the regulatory framework for biosimilars was established in 2012 with the publication of the “Guidelines on Similar Biologics”. The drafters of the guidelines included the drug regulator Central Drugs Standard Control Organization, the Department of Biotechnology, academics, and surprisingly staff of major biotech companies, such as Biocon, Dr. Reddy’s and Roche.
This was a shocking conflict of interest. It is deemed reasonable worldwide to have the industry comment and provide input before the finalisation of regulations that affect public health. But never is the industry allowed to set the standards by which its products are regulated. Even the US Food and Drug Administration seeks public comment but only after the draft guidelines are published.
That conflict of interest was exacerbated by the fact that the guidelines didn’t prescribe rigorous standards needed to establish the safety and efficacy of biologics. For instance, they didn’t include tests assessing the ratio of heavy chain versus light chain of the protein included in the Certificate of Analysis, a legal document that the regulator evaluates for each batch of drug released.
Equally importantly, the guidelines didn’t mention if they were established under the provisions of the Drugs & Cosmetics Act, 1940. As per this law, all technical aspects of drug regulations should be referred to the Drugs Technical Advisory Board, a body with a wide representation of doctors, pharmacists, bureaucrats and researchers. The composition of this board is such that it is unlikely to be influenced by an interest group. It’s unknown if the board was consulted for the guidelines.
What’s also interesting is that the biologics guidelines were publicly announced at BIO, the largest biotechnology conference, in Boston, United States, in 2012. This was perhaps the first time that regulations drafted by Indian authorities for the purpose of regulating drugs in India were announced at an industry event abroad.
Together, these facts raise a crucial question: did the Indian biotech industry set the agenda for the Guidelines on Similar Biologics? This isn’t far-fetched. In 2012, India’s own parliamentary standing committee had accused the Central Drugs Standard Control Organization of acting under the influence of the industry which it is supposed to regulate.
In a sign of the ambiguity over the interpretation of the guidelines, Roche sued the Drug Controller General of India in 2014 along with the pharma companies Biocon and Mylan over the launch of a biosimilar of Roche’s breast cancer drug Herceptin. Besides questioning the approvals granted to the Biocon-Mylan biosimilar, Roche raised doubts over the conduct of clinical trials. All of these questions are now pending before the Delhi High Court, which last year issued a temporary injunction restraining Biocon and Mylan from launching their biosimilar into the market.
Does India have the expertise?
Still, the real challenge in creating a credible regulatory framework isn’t in the drafting of the law or guidelines. It lies in ensuring the regulator has the expertise – the staff competence, leadership and laboratories – to enforce the law. Unfortunately, India has almost no regulatory experience when it comes to complex regulatory approvals.
The two steps of a regulatory approval are the conduct of clinical trials followed by the evaluation of the data generated by those clinical trials. Even on the simple issue of conducting clinical trials, India has struggled to enforce the most basic ethical norm of informed consent. This had prompted the Supreme Court in 2013 to impose a temporary ban on all clinical trials in the country.
Part of the reason for this lack of experience in conducting clinical trials for new drug approval is that the Central Drugs Standard Control Organization depends on regulatory approvals granted in the West for approving drugs in India. The logic is simple: if it’s good enough for the West, we’ll allow it in India. This is why the CDSCO has almost never been the first regulator in the world to approve a new drug. For most of its existence, its only responsibility has been to approve generics, which, unlike new chemical entities, require only simple clinical studies on healthy human beings. Even evaluating the results of these studies is relatively simpler.
That is not the case for biosimilars: clinical trials are mandatory on patients and not just healthy volunteers. Since many biosimilars are being launched in India first, and not in the Western market, the Indian regulator has to actually evaluate data from full-fledged clinical trials to determine their safety and efficacy. Given that the regulator doesn’t have the expertise to conduct such evaluations for even conventional chemical drugs, can we expect it to do an effective job for the vastly more complex biosimilars?
Then there is also the issue of testing laboratories. As things stand, drug inspectors of both central and state governments draw samples from the market and send them to their labs. The government analysts at these labs are required, under Rule 44 of the Drugs & Cosmetics Rules, 1945, to have education in pharmacy or pharmaceutical chemistry or medicine or science. Molecular biology isn’t on this list. There is perhaps only one laboratory in the country, the National Institute of Biologicals in Noida, which has the expertise to test biologicals.
The alacrity with which the Central Drugs Standard Control Organization approved the biosimilar guidelines – and the controversies over them – leads one to question the regulator’s agenda. While the regulator must certainly respect the concerns of the Indian industry, it should not put them before the concerns of patients. If the Indian medical community loses faith in biosimilars because of poor regulation, Indian patients will have to cough up more for foreign imports. The ultimate culprit for this loss of faith will be the regulator.
The author is the executive chairman of Medassure Global Compliance Corporation.
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While it’s appreciable that Indian companies are finally stepping up to their ethical and legal duty of withdrawing unsafe medicine, the episode raises serious questions about the competence of India’s regulatory regime for biosimilar drugs or biosimilars.
What are biosimilars?
For most of the last century, new drugs developed by the pharma industry were based on engineering chemical entities. These were relatively easy to reverse-engineer, giving us the whole industry of generic drugs. And for generic drugs to get marketing approval, they had to clear simple tests to prove their “equivalence” to their original, or “innovator”, counterparts.
Change set in during the 1980s when a breakthrough in the science of gene-splicing sparked off the biotech revolution in the US. For the first time, scientists could manipulate and modify genes to achieve stunning results. They could manufacture human insulin, create genetically modified crops, and ultimately build an entire new class of drugs called biologics.
The science of biologics is completely different from that of conventional chemical drugs. As Fortune magazine describes, biologics “are made using living cells that treat disease, usually by genetically modifying cells. They are big and very complex molecules, often 200 to 1,000 times the size of more common small-molecule drugs”. To explain with an example: aspirin, a small-molecule drug, is made of up 21 atoms, whereas the biologic drug Enbrel, which treats rheumatoid arthritis and plaque psoriasis, is made up of over 20,000 atoms.
As a result of this complexity, manufacturing a biologic is a challenging affair: even a small change in the manufacturing process can cause big changes in the drug’s efficacy. Equally difficult is the process of making an equivalent drug: companies have to find their own way to engineer living cells to provide the same results as the original. These imitations, called biosimilars, are relatively less expensive than the original biologics.
Given all this complexity, it has been necessary worldwide to create a whole new regulatory framework for authorising biosimilars. The kind of simple and limited clinical studies needed for chemical drugs simply don’t work for biological molecules. That is why the global standard for approving biosimilars has been to establish both safety and efficacy independently, because biosimilars are fundamentally different from biologics.
Did the industry drive the agenda?
In India, the regulatory framework for biosimilars was established in 2012 with the publication of the “Guidelines on Similar Biologics”. The drafters of the guidelines included the drug regulator Central Drugs Standard Control Organization, the Department of Biotechnology, academics, and surprisingly staff of major biotech companies, such as Biocon, Dr. Reddy’s and Roche.
This was a shocking conflict of interest. It is deemed reasonable worldwide to have the industry comment and provide input before the finalisation of regulations that affect public health. But never is the industry allowed to set the standards by which its products are regulated. Even the US Food and Drug Administration seeks public comment but only after the draft guidelines are published.
That conflict of interest was exacerbated by the fact that the guidelines didn’t prescribe rigorous standards needed to establish the safety and efficacy of biologics. For instance, they didn’t include tests assessing the ratio of heavy chain versus light chain of the protein included in the Certificate of Analysis, a legal document that the regulator evaluates for each batch of drug released.
Equally importantly, the guidelines didn’t mention if they were established under the provisions of the Drugs & Cosmetics Act, 1940. As per this law, all technical aspects of drug regulations should be referred to the Drugs Technical Advisory Board, a body with a wide representation of doctors, pharmacists, bureaucrats and researchers. The composition of this board is such that it is unlikely to be influenced by an interest group. It’s unknown if the board was consulted for the guidelines.
What’s also interesting is that the biologics guidelines were publicly announced at BIO, the largest biotechnology conference, in Boston, United States, in 2012. This was perhaps the first time that regulations drafted by Indian authorities for the purpose of regulating drugs in India were announced at an industry event abroad.
Together, these facts raise a crucial question: did the Indian biotech industry set the agenda for the Guidelines on Similar Biologics? This isn’t far-fetched. In 2012, India’s own parliamentary standing committee had accused the Central Drugs Standard Control Organization of acting under the influence of the industry which it is supposed to regulate.
In a sign of the ambiguity over the interpretation of the guidelines, Roche sued the Drug Controller General of India in 2014 along with the pharma companies Biocon and Mylan over the launch of a biosimilar of Roche’s breast cancer drug Herceptin. Besides questioning the approvals granted to the Biocon-Mylan biosimilar, Roche raised doubts over the conduct of clinical trials. All of these questions are now pending before the Delhi High Court, which last year issued a temporary injunction restraining Biocon and Mylan from launching their biosimilar into the market.
Does India have the expertise?
Still, the real challenge in creating a credible regulatory framework isn’t in the drafting of the law or guidelines. It lies in ensuring the regulator has the expertise – the staff competence, leadership and laboratories – to enforce the law. Unfortunately, India has almost no regulatory experience when it comes to complex regulatory approvals.
The two steps of a regulatory approval are the conduct of clinical trials followed by the evaluation of the data generated by those clinical trials. Even on the simple issue of conducting clinical trials, India has struggled to enforce the most basic ethical norm of informed consent. This had prompted the Supreme Court in 2013 to impose a temporary ban on all clinical trials in the country.
Part of the reason for this lack of experience in conducting clinical trials for new drug approval is that the Central Drugs Standard Control Organization depends on regulatory approvals granted in the West for approving drugs in India. The logic is simple: if it’s good enough for the West, we’ll allow it in India. This is why the CDSCO has almost never been the first regulator in the world to approve a new drug. For most of its existence, its only responsibility has been to approve generics, which, unlike new chemical entities, require only simple clinical studies on healthy human beings. Even evaluating the results of these studies is relatively simpler.
That is not the case for biosimilars: clinical trials are mandatory on patients and not just healthy volunteers. Since many biosimilars are being launched in India first, and not in the Western market, the Indian regulator has to actually evaluate data from full-fledged clinical trials to determine their safety and efficacy. Given that the regulator doesn’t have the expertise to conduct such evaluations for even conventional chemical drugs, can we expect it to do an effective job for the vastly more complex biosimilars?
Then there is also the issue of testing laboratories. As things stand, drug inspectors of both central and state governments draw samples from the market and send them to their labs. The government analysts at these labs are required, under Rule 44 of the Drugs & Cosmetics Rules, 1945, to have education in pharmacy or pharmaceutical chemistry or medicine or science. Molecular biology isn’t on this list. There is perhaps only one laboratory in the country, the National Institute of Biologicals in Noida, which has the expertise to test biologicals.
The alacrity with which the Central Drugs Standard Control Organization approved the biosimilar guidelines – and the controversies over them – leads one to question the regulator’s agenda. While the regulator must certainly respect the concerns of the Indian industry, it should not put them before the concerns of patients. If the Indian medical community loses faith in biosimilars because of poor regulation, Indian patients will have to cough up more for foreign imports. The ultimate culprit for this loss of faith will be the regulator.
The author is the executive chairman of Medassure Global Compliance Corporation.
