‘Made in India’ medicines: How safe and how effective?

Truth, they say, is often a bitter pill. This book, not an easy read, lives up to the saying. It is also a deeply disturbing book for a country which is supposed to be the pharmacy of the world and where the pharmaceutical sector is growing at a fast clip.

The book rattled India when it was launched in October last year. Days before the launch, the WHO issued a global alert on four cough syrups made in India, after the deaths of 69 children due to acute kidney failure in Gambia.

Laboratory tests found the cough syrups were contaminated with two highly toxic industrial solvents: diethyl glycol (DEG) and ethylene glycol. Within a month, the deaths of 19 children in Uzbekistan were again linked to a cough syrup manufactured by the same firm in India. Once again, the deaths were suspected to have been caused by DEG contamination.

The prologue of the book presciently began with the sub-heading ‘An Epidemic of DEG Poisoning and Regulatory Failure’, giving an overview of recent as well as past instances of such tragedies.

Dinesh Singh Thakur, the first author of the book, is a chemical engineer who turned whistle-blower against Ranbaxy in 2004, the largest Indian pharmaceutical company, after he saw large-scale data fabrication in the company. Ranbaxy pleaded guilty before an American court in 2013, agreeing to pay a penalty of $500 million.

While the West responded about the quality of “made in India” drugs by restricting imports from many Indian pharmaceutical companies, the Indian government’s response was not course corrections or regulatory reforms — it simply dismissed all allegations as conspiracy theories by ‘vested interests’ conniving against the nation. Jingoism and nationalism replaced reforms.

Prashant Reddy Thikkavarapu, the second author, quit his job at a law firm to work full-time with Thakur to undertake research on India’s chaotic drug regulatory system. He was inspired by his mentor, the late Shamnad Basheer, an Indian legal academic who— unlike many cynics—believed that the law, even in India, can be used for the greater good.

While he got the “will” from Basheer, he acquired the “skill” during his studies at Stanford University. Professor Hank Greely at Stanford exposed him to the interface between law and the biosciences. The associations he had with these mentors helped him greatly during the research for this book.

The authors traced back the first instance of large-scale DEG poisoning to 1937 in the USA. Sulpha drugs had recently been invented, and a manufacturer wanted to make a liquid preparation of the antibiotic for children. They ended up using DEG as a solvent, unaware of its poisonous nature. After the drug entered the American market, a total of 105 patients—including 34 children—died. The chief chemist of the manufacturing plant committed suicide.

After this tragedy, drug regulations in the US were made more stringent with focus on safety. The US has never witnessed a single case of DEG poisoning since then. Alas, not so India and other developing countries, including those countries which import drugs from India.

***

DEG poisoning has remained a recurrent phenomenon in the developing world in particular, according to the authors of this hard-hitting book. DEG poisoning killed 7 children in South Africa in 1969; 47 children died of DEG toxicity in Nigeria in 1990, and 84 again in 2018; 236 children died in Bangladesh in 1990–92; 29 people died in Argentina in 1992; 88 children died in Haiti in 1996; and 365 people died in Panama in 2007.

India’s report card on DEG poisoning is equally dismal. It has had five major DEG poisoning events. The first occurred in Madras (now Chennai) in 1972, killing 15 children. The second in Mumbai in 1986 was at the famous J.J. Hospital, killing 14 patients. The third in Bihar in 1988 killed 11 patients. The fourth in Gurgaon in 1998 had 33 children dying after consuming cough syrup contaminated with DEG. The most recent victims were 12 children from Ramnagar, Jammu, as recently as 2019.

According to the authors, these tragedies were entirely preventable. DEG poisoning has been recognised since the instance in the US in 1937, after which there has been no recurrence in that country due to strict implementation of safety measures by pharmaceutical companies, combined with an overhaul of drug regulations. On the other hand, Indian pharmaceutical companies often fail to test either the raw materials or the final product before releasing it to the market, violating the good manufacturing practices (GMP) laid out in Indian law that mandate testing of both raw materials before they are used in production and the final drug sample before mass distribution.

Traders supplying raw material for cough syrups, such as propylene glycol, have sometimes mislabelled DEG as propylene glycol by oversight, or sometimes have used DEG as an adulterant to cut costs. Testing by the manufacturers at critical points could have prevented such tragedies. The authors point out that many small-time pharma companies lack adequate facilities for testing. How they conduct business without basic testing facilities leads to a larger story of corruption and lack of oversight by inspecting agencies.

Over the years, the drug regulations in the country have gone from bad to worse. For instance, the authors note that in 1986, after the death of 14 patients in J.J. Hospital from DEG poisoning, the chief minister of Maharashtra appointed Justice Bakhtavar Lentin, a sitting judge of the Bombay High Court, to head a commission of inquiry into the tragedy.

Lentin produced a document of 300 pages, the infamous Lentin Report, indicting the joint commissioner of Maharashtra FDA and not sparing even the health minister from accountability for the mishap. Lentin’s report received wide coverage in the media. As a consequence of mounting public pressure, the state’s health minister had to resign and the senior officials of the state FDA, including the powerful joint commissioner, were suspended. Senior doctors of J.J. Hospital also faced suspension.

Lentin’s report nails the problems of drug regulation in India. The executive summary of the report states, ‘These pages describe and illustrate the ugly faces of the human mind and human nature, projecting errors of judgment, misuse of ministerial power and authority, apathy towards human life, corruption, nexus and quid pro quo between unscrupulous license holders, analytical laboratories, elements in the industries department controlling the awarding of rate contracts, manufacturers, traders, merchants, suppliers, the FDA and persons holding ministerial rank. None of this will be palatable to the affected quarters. But that cannot be helped.’

However, the reasons for poor quality control of pharmaceuticals extend beyond corruption, as brought out in the subsequent 11 chapters of the book.

***

The first two chapters dwell on the history of drug regulation globally and in India. Chapters 3 to 6 expose the regulatory gaps and failures around not-of-standard-quality (NSQ) products, gaps in regulation of new drugs and issues related to generic medicines — which highlights the conflict between affordability and quality, as well as raising questions on when bioequivalence studies in humans are essential and when in-vitro studies, or a ‘biowaiver’, can suffice.

Chapters 7 and 8 deal with the sensitive issue of traditional medicines. The authors bring out the challenges in this thorny area, due to the lack of a standardised pharmacopeia of traditional medicines. Increasing commercialisation of traditional medicines has led to mass production in tablet or capsule forms for medicines that were earlier dispensed only freshly prepared by vaids (traditional healers). Regulating these is a challenge, as they may contain various added ingredients for nominally the same ‘recipe’.

The authors also highlight instances of adulteration of these drugs with steroids or heavy metals above the prescribed levels and sometimes exaggerated claims of cures. This is a matter which needs attention as many are resorting to alternative systems of medicine in the belief that these are less harmful than allopathic drugs.

Subsequent chapters deal with the chaos of Indian pharmacies and their supply chains, advertisements and promotions, and finally, the challenges of reforming India’s drug regulatory framework in an environment of politics, corruption, archaic regulations and commercial interests.

The authors conclude that democratising regulations, empowering citizens with information and the right to participate and increasing accountability in public procurement are the keys to reform. The public procurement channel, which consists mostly of generic drugs, has shown a high percentage of NSQ drugs, with their percentage in government hospitals being at 10.02 per cent, compared to the overall 3.16 per cent in the generic drug market.

The book has ruffled many feathers. But this bitter pill is necessary if we are to avoid more tragedies. The instances of DEG-associated deaths among children are just the tip of the iceberg. Like the proverbial canary in a coal mine (canaries, sensitive to toxic gases, would be taken inside the mine where they would fall sick or die, providing early warning and allowing miners to escape), the unfortunate children who died from the contaminated cough syrups are warning signs that drug regulation in India is but a myth. 

As a consequence, unsuspecting people in India are exposed to substandard medicines which may be causing long-term damage to their kidneys and liver as all drugs pass through these vital organs. These long-term adverse effects may go undetected.

The book dwells at length on the regulatory system in India, which consists of the Central Drugs Standard Control Organisation (CDSCO) and 36 state-level regulatory agencies. The CDSCO deals with new drugs, clinical trials and imported medicine. The state authorities issue licences for the manufacture, sale and distribution of drugs. An important role of the state authorities is to carry out periodic inspections. This is supposed to prevent manufacture and distribution of spurious or adulterated drugs.

Since Independence, the buck is being passed to and fro between the central and state agencies, with ill-defined roles and lack of accountability in implementing regulations. Inter-state jurisdictional ambiguities also give rise to many loose ends. Ill- defined hierarchies between the CDSCO and the state drug authorities lead to lack of accountability. This results in poor regulations and lack of uniformity in quality of drugs across India. The chaos is covered by the opacity of regulatory bodies. Information is difficult to access and the authors had to file over 400 applications under the Right to Information (RTI) Act to collect data for the book.

The authors also rue the lax and lenient implementation of the letter of the law. Manufacturing drugs that are not of standard quality (NSQ) is a serious offence, punishable by imprisonment and hefty fines. But often, as documented in the book, judges impose a fine of a few thousand rupees and a sentence of “simple imprisonment till the rising of the court”!

An important omission in this otherwise extensive treatise is an appraisal of the pharmacovigilance programme in the country. A robust ongoing monitoring system of the adverse events of drugs after they are released in the market can give an early warning of drug toxicity.

Comment on this would be especially pertinent also to scotch rumours around the (alleged) adverse effects of new vaccines and drugs.

Dr Amitav Banerjee, MD, is an epidemiologist and has served for two decades in the Indian Armed Forces. He is currently a professor at D.Y. Patil Medical College, Pune.

END