The Indian Pharmaceutical Alliance (IPA) on Wednesday dismissed the claims of US-based study that found that generic medicines manufactured in India were associated with a 54 percent higher number of serious adverse events (SAEs).
“We strongly disagree with the study’s premise that differences in operations and supply chain factors — suppliers, manufacturing and/or distribution practices by different manufacturers — impact the quality and efficacy of Indian generic drugs,” IPA stated.
The pharma body said that FDA follows a stringent process of inspections both for manufacturing sites based within the US and outside in emerging geographies, notably, in India.
In the last decade, there has been a significantly greater engagement that the Indian industry and the regulator have had with the FDA in addressing manufacturing and quality operations in the Indian subcontinent and some of the outcomes are reflected in the post-inspection categorisation of the facilities. The inspection outcome categorisation of Official Action Indicated (OAI) has reduced to 11% in 2024 compared to 23% in 2014 for Indian companies, in line with the global trend of 14% in 2024.
“Indian manufacturing facilities are subject to far greater scrutiny as most manufacturers supply products to multiple geographies and are inspected additionally and routinely by the regulators from European Union, UK (MHRA), Australia (TGA), Brazil (ANVISA), Health Canada and several others all of which hold high quality standards and share findings under mutual agreement,” it stated.
IPA also stated that while generics are priced lower than the corresponding brands, it is unfair and unacceptable to link quality with cost. IPA represents 23 major national pharmaceutical companies. Collectively, IPA members account for over 85% of private sector investment in pharmaceutical research and development, drive more than 80% of India’s drug and pharmaceutical exports, and serve over 64% of the domestic market.
“India’s competitive cost is on account of automated high-production capacity plants, continuous process improvement, inherent cost advantage in manpower and manufacturing synergies including scale of operations. Many products are backward integrated to the actives, realising better cost efficiencies,” it added.
The study also appears to be ill-researched, claiming lack of transparency in drug manufacturing location for Indian generics, it pointed out.
“Complete manufacturing address by law is indicated on every single pack of generic products distributed in the US market, besides being available on FDA’s database, such as the Orange Book. An exception to this rule is Over the Counter (OTC) products distributed by private label distributors like Walmart, even those which indicate India as the country of origin,” IPA said.
According to IPA, the report relies upon the FDA Adverse Event Reporting System (FAERS), the post-marketing surveillance database for adverse events. FAERS data is observational, and thus captures associations between drugs and adverse events but does not prove causation. Therefore, a higher rate of serious adverse events (SAEs) for drugs manufactured in emerging economies does not inherently mean manufacturing quality is inferior.
For the analysed data, the authors admit that there are limitations in terms of the information available in the report that may not have been medically confirmed, or that conditions other than the suspect drug may have caused the event. So, a lack of correlation can be observed between the incidence of reported SAEs and the medicinal product, it added.
“The purpose of pharmaco-vigilance (PV) reporting is to capture safety signals so that physicians are appropriately made aware of any additional information about the drugs and to ensure safe medication is prescribed to the patients. Where necessary, the adverse observations form the basis of inclusion into prescribing information mandated by FDA. We disagree that adverse event reporting can be related to manufacturing for following reasons:
PV events are generally a reflection of the properties of the active drug substance and the drug product, irrespective of where it is manufactured. Thus, it cannot be conclusively linked with the manufacturing site or manufacturers.
The reporting to the US FDA is governed by 21.CFR.314.80 and necessitates both domestic and foreign reporting. This means that if an ANDA holder (generic product manufacturer) has a product registered in the US and there is any adverse effect reported for any dosage form of that molecule anywhere in the world, irrespective if the manufacturer sells/doesn’t sell the product in that market, FDA mandates the ANDA holder to report it if it is serious and unexpected case under the approved ANDA number resulting in over reporting.
Reporting of the adverse events is not dosage form specific, thus if there is an adverse effect reported on say tablets (oral solid dosage) and the ANDA holder has capsules or injection registered in the US, they will still have to report to FDA; these may be manufactured at different facilities, even outside emerging markets/India.
Many cases reported in the database are from doctors/healthcare professionals that are reported in published literature, which ANDA holder will have to report to FDA against their own ANDA. Such a product may have been manufactured anywhere in the world, even in the US.
It is not clear if reporting by multiple applicants has been nullified. Since Indian industry leads generic supplies in the US, there will be multiple reporting of the same adverse events from India, adding up to the numbers.
“There are many factors leading to adverse events that are reviewed during causality assessment by medical doctors, including concomitant medications and medical history of the patient (disease factors) and cannot always be conclusively ascribed to the drug. The authors should have taken the causality assessment of adverse events into account instead of attributing these to manufacturing location, supposedly driven by operations and supply chain factors,” IPA said in its statement.
The pharma body also said that use of FAERS to conclude product quality has limitations—reporting biases, lack of denominator data, and inability to establish causality—that make it unsuitable for the purpose. The study employs considerate methodologies but remains constrained by the purpose and limitations of FAERS data.
“We believe that FDA mechanism of product approvals and enforcement of quality through various measures including routine inspections adequately address product quality. Quality is fundamental to pharmaceutical operations. The Indian pharmaceutical sector has made significant strides in strengthening quality systems in response to evolving global regulatory expectations,” it stated.
There have been recent developments in Quality Maturity (adherence to regulatory standards, risk-based approaches, and a proactive quality culture) in India. The Indian pharmaceutical industry is committed to holding the highest standards in quality and prioritizing patient safety and well-being,” it added.