Serial testers: India's flawed generic drug trials business

Vasudeva Prakash left his job as a mechanic in Hyderabad three years ago for what he calls a more lucrative career: taking part in clinical trials on generic drugs.

For two years, Prakash participated in trials of drugs being tested to treat HIV/AIDS and other diseases for contract research organizations (CROs) hired by global pharmaceutical companies. The drugs tested at Indian CROs have been key in getting several hundred medicines approved for sale around the world.

Yet, Prakash did not follow international guidelines for testing and the CROs that hired him didn’t require him to. He says that to earn more money he would participate in back-to-back trials on different drugs with gaps of only a few weeks or even a few days, instead of waiting the 90 days that the World Health Organization recommends.

Half of more than a dozen volunteers interviewed by Reuters across four cities: Chennai, Hyderabad, Bengaluru, and New Delhi also said they waited much less than 90 days between trials. In the past three-to-four years, they said they spent several months at a time in different cities so that they could participate in as many studies as possible.

Prakash provided documentation proving he underwent trials with short gaps at Apotex Research Pvt Ltd, owned by Canadian drugmaker Apotex Inc; Lotus Labs, owned by U.S. generics giant Actavis; Ethics Bio Lab, owned since last year by U.S. drugmaker Par Pharmaceutical Inc; and India’s Semler Research Center Pvt Ltd, among others. Ethics Bio and Apotex did not respond to requests for comment. Lotus Labs and Semler said they had systems in place to check for cross-participation by trial volunteers.

The guidelines of the WHO, which decides on approvals for drugs sold in several countries dependent on United Nations programs for basic medicines, are not legally-binding for the CROs. While India has guidelines on clinical trials, they don’t specify the length of time participants should take between trials.

Still, the serial testing of some volunteers is raising new questions about the level of oversight of India’s generic drug trials industry, after some CROs came under recent international regulatory scrutiny. Last year, the European Medicines Agency banned about 700 medicines across Europe after an investigation revealed data tampering in some trials of generic drugs in India.

International medical experts said that undergoing back-to-back trials endangers the health of patients participating. It can also compromise clinical data gathered through these trials, on the basis of which drugmakers seek approval to sell generic medicines around the world.

“The time gap between participation in two different trials should be 90 days minimum,” said Stephanie Croft, a lead inspector at the WHO. “When [data] is incomplete or incorrect it could pose a serious risk to patients.”

Gyanendra Nath Singh, head of India’s national drug watchdog, the Central Drugs Standard Control Organization (CDSCO), said that it has been trying to inspect more CROs in the past two years. The watchdog is also considering the introduction of a track-and-trace system through which patients can be tracked across CROs, he told Reuters.

“We are emphasizing on good regulatory practices some reports have shown that the CROs have deviated from (the) system,” said Singh.

India's Health Ministry did not respond to requests for comment.

GLOBAL REACH

Several large international drugmakers, including Teva Pharmaceutical Industries Ltd and Mylan NV, rely on CROs in India to carry out tests on cheaper versions of branded drugs. The aim of these so-called “bioequivalence” studies is to gauge whether non-branded drugs are equally safe and effective. The faster the trials are undertaken, the faster the drugs can come to market.

In some major markets, such as the United States, being the first to launch a generic guarantees market exclusivity for a period of time, which can reap millions more in sales.

International and local regulators have struggled to keep its oversight in line with the growth of an industry that expanded rapidly in the 2000s, as drugmakers shipped clinical trial work to India to save money. The market is estimated to have crossed $1 billion in 2016, according to consultants Frost and Sullivan.

Over the past two years, international regulators have suspended or banned medicines tested by four major Indian CROs after finding manipulation of clinical trial data and other violations.

Issues found at Indian CROs are "a big problem that is gaining more and more attention from all sorts of agencies," said Anders Fuglsang, a consultant and former regulator long involved in audits and inspections of CROs around the world on behalf of international regulatory agencies and companies.

Last year, the European Union banned about 700 medicines that had been approved based on clinical trial data provided by GVK Biosciences, then India’s largest CRO. European regulators said they found GVK had manipulated data concerning the heart readings of patients taking part in the study. GVK denied any violation, but several large drugmakers that had won drug approvals based on GVK’s data were asked to re-apply for approval with fresh evidence.

Such re-testing is a headache for drugmakers, as it is expensive, and delays lead to a loss in sales, said Nilesh Gupta, managing director of India’s Lupin Ltd, which was one of the companies to be affected by a US ban on trials by Semler earlier this year.

GVK, part of the Indian conglomerate GVK Group, has since limited its business interests in the generic drugs testing business, said Shankar Chelluri, a spokesman for the company. Overall, sentiment towards the generic drug trials business is weak, Chelluri said.

Another CRO, Quest Life Sciences, was found last year to have manipulated clinical data on certain trials, according to inspection reports from the WHO and the UK’s medicines authority. The Spanish and German regulators had also found problems with Quest’s trials, and the WHO said it found Quest had falsified data on drugs including the antibiotic doxycycline hyclate and HIV/AIDS drugs lamivudine, zidovudine and nevirapine.

Quest managing director TS Jaishankar said his CRO, which has conducted dozens of generic drug trials for companies including India's top drugmaker Sun Pharmaceutical Industries, has since invested heavily in improving its systems and been cleared by all international regulators. In a response to Reuters, a spokeswoman for the European Medicines Agency said they were “closely monitoring” the involvement of Quest in the drug approval applications they receive.

India, like other countries, has ethics committees groups of independent experts meant to approve the design and conduct of clinical trials. Their stamp of approval is required by foreign regulators considering allowing a generic drug to be sold. However, these committees depend on the CROs for reimbursement in exchange for reviewing trials. Three members of different committees Reuters spoke to said national guidelines did not clearly define their roles and responsibilities.

In the wake of trial data manipulation scandals at CROs in the past three years, many large drugmakers including Swiss firm Novartis, have been shifting more critical trials back to the United States and Europe, according to consultants and industry executives.

Novartis is also ramping up its own checks of Indian CROs, said Bodo Lutz, a data integrity officer at the Swiss firm. Speaking on the sidelines of a conference in Hyderabad in July, he said: "We can't rely on the regulators ... we're increasing our own audits."

VOLUNTEERING "LIKE AN ADDICTION"

Prakash, the former mechanic, said he was never asked by CROs, and their ‘agents’ who approached him for studies, about whether he had recently taken part in another trial.

"Everybody does it. Once you start getting the money, it's very hard to quit. It's like an addiction," said Prakash.

He said after the first study, he began to regularly receive messages on his phone and Facebook, often from agents working on behalf of CROs, informing him about ongoing clinical trials where volunteers were required. Such messages included three key things: the city where the trial was being conducted, the total pay offered, and the “blood loss”, or the amount of blood the volunteer will need to provide.

Venkatesh, from the southern city of Tirupathi, described travelling from Chennai to Hyderabad and then to Bangalore and Mangaluru for different trials.

"I know of several people who participate in three or four trials in the same month," said Venkatesh, who stopped volunteering two months ago and has since married. He did not want to be referred to by his full name.

Prakash said he was paid 10,000-30,000 rupees ($147-$441) per trial, depending on the duration and type. He stopped participating after his health began to deteriorate last year at age 25.

He now works at a call centre earning 20,000 rupees a month, but, despite knowing the risks, entered two more trials recently to raise cash.

"I needed some money desperately so I did it, but I won't do it again," he said.