By

Dinesh Thakur and Prashant Reddy T.

On March 25, 2023 the Economic & Political Weekly (EPW) published a review of our book – The Truth Pill: The Myth of Drug Regulation in India by Dr. Anant Phadke, a co-founder of the All India Drug Action Network and a trustee of Low Cost Therapeutics (LOCOST), a pharmaceutical manufacturing enterprise based out of Baroda, Gujarat.

This book review is problematic for many reasons, the most obvious one being the fact that EPW has not made some key disclosures. For instance there is no disclosure in the review that Phadke and his fellow activists are a subject of critique in our book because of the very obvious conflict of interest they face in their dual roles at trustees of LOCOST and co-founders AIDAN. Would a public health activist advocate for stricter punishment for the manufacturers of sub-standard medicines if the activist was also sitting on the board of a pharmaceutical manufacturer? Most definitely not; and Phadke is the perfect example as we will demonstrate in this piece.

A second disclosure not made in the review, is that our book has pointed out how LOCOST and Srinivasan (co-founder of AIDAN) have been convicted by a Chief Judicial Magistrate, Pune for the crime of manufacturing sub-standard drugs used for treating hypertension. LOCOST’s drugs were found to have only 36.5% of the active ingredient mentioned on the labelling. Untreated hypertension can cause strokes and heart attacks. The punishment that followed the conviction was quite paltry. The court imposed a fine of merely Rs. 10,000 and simple imprisonment till the rising of the court. This, when the law requires a minimum of one year punishment unless there are “special” reasons, which the magistrate has to justify in writing. As we have pointed out in our book, LOCOST is not the only beneficiary of this lenient sentencing policy – this is a standard sentencing practice in at least Maharashtra, Karnataka and Tamil Nadu. To have a trustee, like Phadke, of an enterprise convicted of manufacturing substandard drugs, actually write a review of a book on drug regulation without disclosing the fact of the conviction is a serious breach of editorial ethics on part of EPW. But it gets even more problematic. In his review, Phadke mocks our criticism of such lenient sentencing practices. He states in his review:

“But the authors unjustifiably deprecate that many judges use the proviso in the current Drugs and Cosmetics Act (Section 27) of punishment for less than a year (“if the court feels for adequate and special reasons to be recorded”), including punishment of “imprisonment till the rising of the court.” They seem to imagine that they have a better understanding of justice than all the concerned judges.”

Our criticism, unlike Phadke’s understanding, was grounded in the standards laid down by the Supreme Court in a series of precedents where the court discussed the meaning of “special reasons” and criticised the general leniency shown by magistrates towards white collar crime. (p. 102-103) In all the judgments we came across in our research, including the LOCOST case, the criteria laid down by the Supreme Court was never met.

Even more astonishing are Phadke’s views on criminal penalties for the manufacturers of sub-standard drugs. He claims that our demand for prosecution of every case is unjustified because manufacturing defects are known in every industry and that any prosecution should be preceded by an investigation to establish whether there was criminal intent, mala-fide intention, negligence, genuine mistake or incompetence. Manufacturing defects in the case of drugs have serious consequences for the health of patients and cannot be compared to other products. More pertinently Section 27(d) of the Drugs & Cosmetics Act, 1940 requires absolutely no assessment of criminal intent or lack of it. As long as the drug fails quality testing, the manufacturer is to be prosecuted and convicted. That is the law.

Should it be reformed? Yes, there is room for rethinking the nature of criminal punishments, as we accept in our book but until the law is what it is, it should be followed. More worrying is the fact that the pharma industry has been lobbying for complete decriminalisation through the Jan Vishwas Bill – a move that both of us oppose and have written about publicly in the Economic Times. AIDAN on the other hand has maintained silence on the issue perhaps because their co-founders who are on LOCOST’s Board will no longer face the threat of jail time under the new provisons. Without adequate disclosures by EPW, a reader will not fully appreciate this nuance while reading the book review. This is why editorial disclosures are absolutely necessary.

Misrepresenting the arguments in our book

Lack of disclosures apart, there is also the issue of illogical and misrepresentative arguments made by Phadke in his review. For example, he begins with the grand claim that there is a great conceptual confusion in our book when we discuss the issue of generic drugs. He claims that there are two definition of generic drugs – one that deals with drugs that are off-patent and the other is the category dealing with drugs that lack a brand name. He then proceeds to accept that the second category does not exist in India, stating “If the authors imply the second meaning, there are almost no generic medicines in the Indian retail market”. If the second category does not exist in India, why would anybody discuss it? It would be illogical to do so. Leaving that aside, Chapter 6 of the book is crystal clear that we are dealing with off-patent generic drugs.

The other issue that Phadke repeatedly misrepresents in his review is that we are not clear on whether we are criticising Indian or foreign generic medicine. At one point he states: “The authors do not seem to realise that their allegation of Indian generic medicines being “substandard,” also applies to the off-patent medicines made and marketed by the Western MNCs in India.” At another point, he references Indian exports to the US and UK and states “The authors overlook the fact that these manufacturers exporting generics to regulated markets are very much part of the Indian generic industry.” This is a longstanding problem with Phadke and also AIDAN – both seem to view Indian generic companies as saints and foreign MNCs as sinners. On the other hand, our book has never taken this approach of going after either MNCs or Indian companies. It is a fool’s errand, in our opinion, to try and label different companies based on the nationality of their shareholders. This is exactly why our book is not about individual companies – it is about regulatory law and institutions in India. We harp on how India did not have basic regulations for bioequivalence and stability tests for generics drugs because of which much of the medicine made in India could not be trusted. Much of our criticism in the book will not apply to generics being exports to developed countries because those exports are governed by foreign regulations in developed countries, which are generally more rigorous compared to India. 

The most startling misrepresentation in the book review is Phadke’s discussion on bioequivalence testing, since it is this issue that forms the basis of his most serious accusation against us: “Overall, these pages in the book unwittingly serve the interests of the big pharma/MNCs.”

To provide some context, one of the issues we raise with regard to regulations for approval of generic medicine in India, is the fact that bioequivalence studies were not mandatory until recently (2017). Bioequivalence studies evaluate the rate at which drugs are absorbed by the bloodstream of a human. If it dissolves at the same rate or about the same rate as the already approved reference product, it is deemed to be bioequivalent. Not all drugs require bioequivalence testing in humans and some drugs that qualify for “biowaiver” can be tested in laboratories for surrogate parameters. We dedicate about three and a half pages explaining the concepts of biowaivers, starting with the first scientific papers that discussed this concept. We also clearly state that “granting biowaivers could certainly open the door to a more affordable regulatory pathway” but we justify this optimism with detailed caveats on the steps required to make sure biowaivers are effective. 

But if you were to read Phadke’s review without reading our book, you would come away with the impression that we have not even mentioned the word “biowaiver” in our book. In pertinent part, he points to an excerpt we reproduce of an expert committee to make bioequivalence testing compulsory before triumphantly declaring our argument as the “half-truth” because the committee also recommended biowaivers. Nowhere does he mention that we spend three and half pages discussing biowaivers, their acceptability and the issues regarding the government’s failure to clearly identify markers for biowaivers. He repeats this brazen lie towards the end of the review when he states:

“Moreover, the authors’ unscientific, exaggerated, across-the-board insistence on costly, bio equivalence studies (which also implies the use of India’s poor people as guinea pigs in huge numbers) as a precondition for permitting the manufacture of generic medicines”.

Phadke’s entire basis for the above accusation against our work is this out of context sentence that he reproduces in his review “bioequivalence testing for all generic drugs”. His review claims this sentence is on page 215 but we check page 215 and this phrase is not on that page. We presume he meant page 234 where this phrase does appear. But if Phadke was relying on page 234, his allegation is a brazen misrepresentation because that sentence on p. 234 is in context of a paragraph where we discuss how India initially made bioequivalence testing only for those generics in the “new drug” phase approved by the DCGI, while generics approved by states post the “new drug” phase did not require bioequivalence testing. For example, generic Glivec approved by the DCGI in 2004 would require bioequivalence testing but if a different manufacturer sought approval for their generic version of Glivec in 2010 from a state drug controller, they would not be required to submit bioequivalence testing data for approval. How does this make any sense? It is in this context that we make the argument that all generics require bioequivalence testing. Anybody reading that chapter, would come away with that understanding and also understand how we support biowaivers with certain caveats.

The final problem with Phadke’s review and this is unfortunately a common problem with reviews in India, is a complaint that we did not cover topics that he thought were important, namely the political economy of India’s pharma industry and the drug pricing issues in India along with our apparent failure to “appreciate” Indian pharma’s contribution to increasing access to medicine. This is a rather silly line of criticism because there already are books written on these issues. A history of the Indian pharma industry, partly exploring the political economy, was written by Sudip Chaudhari and published by OUP in 2008. On drug pricing, Ajay Bhaskarbatla has written an extensive book that was published by Springer in 2018. So why exactly should we be addressing these issues in a book on drug regulation and quality? The rather unfortunate answer is that several people in this country, especially access to medicine activists believe that is fine to manufacture substandard medicine as long as it improves access to medicine. As we ask rather pointedly in our book, of what use is medicine that does not work to cure disease?

Phadke’s book review and EPW’s decision to publish it without disclosures reflects poorly on both parties. EPW offered to publish a response but we have no intention of doing so because we simply do not trust EPW’s editors to be fair after their failures to make required disclosure about Phadke’s involvement in drug regulation in India. They have so far not accepted responsibility or apologised for publishing Phadke’s review without making the adequate disclosures.

Over the last year, India has witnessed many astonishing approvals granted by its drug regulator CDSCO. Most of these approvals have been wrapped in mysterious legal lingo like ‘restricted emergency use’ and ‘clinical trial mode’ despite Indian law never using such terms. The most astonishing of these approvals is the one granted to Bharat Biotech’s Covaxxin despite the company’s admission that efficacy data from the ongoing clinical trial will not be available until March 2021.

The only discernible reason it appears for this unholy rush in defiance of good science or medical ethics is the government’s obsession with its ‘Atmanirbhar’ agenda which is a version of economic nationalism that has many takers in the country.  

Of course, any criticism of the drug regulator’s whimsical ‘decision making’ process by doctors, scientists and journalists has been met by the establishment’s acolytes, with accusations of ‘vested interests’ and dollops of ‘anti-national’ rhetoric. The Atmanirbhar agenda apparently triumphs public health. None of this surprises me.

Many years ago, when I blew the whistle on Ranbaxy’s fraudulent practices which led to the company’s prosecution by the US government and its eventual guilty plea before American courts, I waited with bated breath to see whether and how the Indian government would prosecute Ranbaxy. After all, much of the fabrication and fudging of drug safety data, that the company pled guilty to took place on Indian soil and people of India were amongst the consumers of Ranbaxy’s adulterated drugs. Imagine my surprise when the then UPA government put out an official press release blaming “vested interests” who were apparently out to destroy the reputation of the Indian pharmaceutical industry. This after the company’s pled guilty to seven counts of criminal felony and paid up $500 million in penalties! A few years later when I filed a petition before the Supreme Court asking for reform of India’s drug regulatory framework, the then Drug Controller General of India is on the record questioning my ‘nationalism’. What does nationalism have to do with a company fabricating quality & safety data for drugs that is selling in India and abroad? Framing the issue of ‘drug regulation’ in the language of nationalism is a dangerously cynical ploy. Drug regulation is about science, medical ethics & patient safety.

The science of how drugs and vaccines work on the human body does not change across borders. After all science is the universal pursuit of truth. History has shown us how new drugs, even vaccines can be dangerous if not tested properly. The thalidomide tragedy of the sixties led to the birth of thousands of deformed babies and deaths of many more. Merck’s blockbuster drug Vioxx was withdrawn after it became clear that the drug increased the risk of heart-attacks and strokes. Rotravirus vaccines, including ones developed in India, have run into trouble because of their alleged association with an increased risk of intussusception in babies. It would be a mistake to presume the safety or efficacy of vaccines without large scale clinical trials. Even with the COVID vaccines, it should be remembered that apart from the Pfizer, Moderna and Astra-Zeneca/Oxford vaccine candidates, most of the other vaccine development efforts in the Western world have run into rough weather and are several months away from approval.           

As for medical ethics, these are principles that have evolved in the light of horrifying tragedies, many of which were due to the evil of men and some due to the inherent risks of experimental science. These include medical experimentation on Jewish women by Nazi scientists like Eduard Wirths, the Chief Physician at the Auschwitz concentration camp during World War II and the Tuskegee syphilis experimentation on African Americans in the United States. Closer to home, we have seen significant violations of ethics during clinical trials for HPV vaccines carried out on tribal girls in Chhattisgarh. In each of the above cases, it was vulnerable communities – Jews, women, tribals, children, African Americans – who have been exploited by not just pharmaceutical companies but also “well meaning” scientists and doctors. Medical ethics exist in the law to protect the rights of these marginalized communities in a deeply unequal world. To ignore medical ethics is to ignore the rule of law.  

India has never had a viable anti-vaccine sentiment unlike countries like the US. The success of national vaccination programs which are largely responsible for eradication of diseases like Polio from the country are a testament to this. Sadly, the preliminary data from the Covid-19 vaccination program is not encouraging. On the first day of the vaccination campaign, Delhi recorded an achievement of 3369 people who got their shots compared to their daily target of 8139. It appears one of collateral damages of this adventurism in the approval process is increasing vaccine hesitancy that we are seeing today; something the country can ill-afford during these trying times.

Inoculating people with vaccine candidates not tested exhaustively for safety and efficacy is a recipe for a disaster. Not only will it adversely affect public health but it will also seriously impact the long-term confidence that the world reposes in Indian science. If anything, it hurts the government’s ‘Atmanirbhar’ mission. Trust in science and experimental medicine is built by regulators following sound science and the rule of law. Nationalism should have no place in such debates. As the saying goes, nationalism is the last refuge of the scoundrel, more so when it is raised in context of drug regulation. Beware of those who wave this flag of nationalism when it comes to the safety and efficacy of medicine that you intend to give your children. The only silver lining in these times are the voices of the many doctors, scientists and journalists who have called the regulator out on its arbitrary decision-making process.  

An abridged version of this piece appeared in The Telegraph on July 27, 2020.

In a break from regular procedure to approve new drugs, the Drugs Controller General of India (DCGI) recently granted an approval to Biocon Ltd. without the mandatory Phase III clinical trial. According to the company, it conducted a Phase II study on a cohort of 30 patients. This therapeutic candidate, Itolizumab is an anti-CD6 monoclonal antibody that was previously approved by the DCGI for the treatment of psoriasis, which is a skin disease. The status of this drug in foreign markets is unclear.

After receiving the DCGI approval, Biocon’s top brass promoted the drug through social media channels and television interviews. Spokespeople for the drug manufacturer used adjectives like “breakthrough drug”, “compelling outcome”, “life-saving”, “unique” to tout the efficacy of this drug in treating COVID-19 during their promotional campaign. It was left to Indian Council of Medical Research (ICMR) to dispute some of these statements in a press conference where its Director General said that there was no evidence from clinical studies to show that this drug reduced mortality amongst severely ill COVID-19 patients.

The DCGI’s actions have raised eyebrows in the public health community because this is one of the few times that the Indian Regulator has approved a drug for a specific indication before the regulatory authorities in the US or the EU and has waived the conduct of Phase III confirmatory studies. Medical doctors, clinical scientists and those who have experience in drug development and public health have asked questions about this approval because a waiver of Phase III clinical trials is unheard of in the medical community even during public health emergencies. There is an unease that this approval will be used as a precedent by others seeking to circumvent the mandatory requirement of rigorous Phase III clinical trials to demonstrate an acceptable benefit-risk profile for any therapeutic candidate.

It is important to understand the role of a properly designed and conducted a Phase III clinical study in drug development. Unlike a Phase II study, which is the subject of this controversy, a large, properly randomized Phase III study helps us answer what truly is the therapeutic efficacy of the experimental drug while considering its risks (side effects). It is also the riskiest phase of drug development as a large percentage of drug candidates that make it through Phase II fail during a Phase III study. Such a study often demands a patient cohort of hundreds and often thousands of subjects in order to show meaningful statistical differentiation from a random chance of recovery from the disease. For example, the dexamethasone studies that recently demonstrated a significant reduction in deaths of COVID-19 patients recruited 6,400 patients of whom 2,100 received dexamethasone, while the remaining received standard care. Phase III clinical trials for Remdesivir were carried out in two stages, the first involving 397 patients and the second which began with 600 patients and was later expanded to 1,000 patients. The results of these trials for both dexamethasone and Remdesivir were published in reputable peer reviewed journals while their approval was being considered by regulatory bodies. Biocon in contrast got the approval from the DCGI based on a clinical trial which had a cohort of just 30 patients and we are yet to see any studies published in a reputed peer reviewed journal.  Epidemiologist and public health physician Jammi Nagaraj Rao explained the true size of patient cohort needed to demonstrate if the study were to meet its primary endpoints for reduction in mortality rate or to have compelling data.

Given these well-founded concerns over the waiver of Phase III study for this approval, it is necessary to understand how drug approvals in India have reached this slippery slope where pivotal Phase III trials can be waived based on such small Phase II studies. The only publicly available information about this drug’s approval, due to the inherent opacity of India’s drug regulatory framework, are the minutes of the Subject Expert Committee (SEC) which advises the DCGI on new drug approvals. The minutes for the SEC meeting where Biocon’s drug was approved do not even reveal the names of the experts who participated in the meeting and reviewed the data from Biocon. The minutes also do not list any clinical or statistical reasons for waiver of Phase III studies. Rather, they note that Biocon’s drug was being approved for ‘Restricted Emergency Use’. However the New Drugs & Clinical Trials Rules, 2019 under which Biocon’s drug was approved does not have any clause like its American counterpart, where drugs can be authorized for ‘Restricted Emergency Use’ under section 564 of the Federal Food, Drugs and Cosmetics Act.

Under Indian law, there are two other alternative pathways for approval of drug candidates that have not been evaluated in Phase III clinical trials. The first is the ‘accelerated approval’ procedure in the Second Schedule of the New Drugs & Clinical Trials Rules, 2019. To secure an approval under this pathway, pharmaceutical companies have to show that their experimental drug candidate demonstrated ‘remarkable efficacy’ during the Phase II trials for a disease that lacks alternative treatments and that there is a prima facie case of meaningful therapeutic benefit over the existing treatments. Given the small patient cohort for this study, it would be important to understand how the SEC determined “remarkable efficacy” of this drug candidate if it was approved using this pathway. To our knowledge, this pathway has never been used earlier in India. In the U.S., even when a drug gets ‘accelerated approval’ its manufacturer is still required to conduct Phase III studies to evaluate the drug candidate’s benefit-risk ratio – there is no question of a waiver.

The second regulatory pathway is laid down in Rule 91 where an ‘unapproved drug’ maybe manufactured in India for treatment of patients with life-threatening diseases. There is no discussion of waiver of Phase III trials under this provision. Therefore, it is not clear under which of these two provisions did the SEC and the DCGI grant “Restricted Emergency Use” for Biocon’s drug candidate and the DCGI is doing little to clear the confusion.

Observational data (Phase IV studies) is no substitute for properly designed and controlled Phase III studies.

The lack of transparency and the ease with which the basic norms of evidence-based approval of drugs are being thrown to the wind by the DCGI is worrying because India has had a troubling history of new drug approvals. The 59^th report of the Parliamentary Standing Committee on Health had exposed many scandals in how new drugs were approved – this included the approval of drugs that had not been approved in the Western world. There is then the report of the Mohapatra Committee which was constituted to inquire into the questionable approvals pointed out by the Parliamentary Standing Committee. It took us two long years, a rather trying process to get a copy of the report that singles out three former DCGIs by name for granting these approvals which have no scientific or clinical rationale.

This pandemic has exposed the dysfunction in the country’s regulatory system that has always thrived on the patronage of the pharmaceutical/ayush industry and brought its true nature into sharp focus to a much wider audience than is often interested in how the Ministry and the Drug Regulator function. The past few weeks have witnessed a gross violation of the Drugs and Magic Remedies Act by the makers of Coronil with little to no consequence and the approval of Favipiravir based on sparse clinical data. As concerned citizens we are well within our right to ask questions of the DCGI about its new approval without being accused of undermining national interest and we hope the government will respond constructively to our concerns.