HYDERABAD, India – A number of drug companies in India may have to repeat expensive clinical trials after Bangalore-based contract research organization (CRO) Semler Research Center Pvt. Ltd. received warnings from both the World Health Organization (WHO) and the FDA in April over data manipulation.

“There are a number of things companies look for in CROs – high level of integrity, speed of execution, operation efficiency and skillsets which are very specific for [a] molecule’s integrity,” Sujay Shetty, Pricewaterhousecoopers’ leader in the pharmaceutical and life science sector, told BioWorld Asia. “When companies have to repeat the clinical studies, they have to put in all the time and resources again, not to mention the disruption of the market it causes. So it’s a considerable payment.”

Semler conducts bioequivalence and bioavailability studies for several pharma companies in India. Instances of data manipulation and poor-quality chromatographic studies came to light during an inspection by a WHO prequalification test team from Jan. 27, 2015, to Jan. 31, 2015, and an FDA inspection conducted between Sept. 29, 2015, and Oct. 9, 2015. The products tested included drugs for HIV, malaria and tuberculosis (TB).

In a recent note of concern (NOC), the WHO said the “investigations revealed critical and major deviations” from good laboratory practice (GLP) and good clinical practice GCP). The agency found serious lapses on two fronts: in data integrity, including evidence for manipulation of study samples regarding some HIV drugs; and poor quality of chromatography studies regarding the malaria drug artemether.

“Manipulation of at least five studies over an extended period of time indicates this is a common practice,” said the WHO in the NOC, and the manipulation is “not confined to a single person operating outside of the quality management system.”

The WHO’s prequalification team concluded that “medicines whose data is manipulated or otherwise associated with implausible evaluations are associated with unquantifiable risks due to unknown safety and efficacy and thus cannot be trusted to bring patients the desired level of benefit.”

Meanwhile, a separate letter from the FDA notified sponsors of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) that clinical and bioanalytical studies conducted by Semler “are not acceptable as a result of data integrity concerns,” and need to be repeated.

The FDA inspection found “significant instances of misconduct and violations of federal regulations, including the substitution and manipulation of study subject samples.”

The medicines that formed part Semler’s flawed studies include fixed-dose combinations of the HIV drugs efavirenz, lamivudine and tenofovir, zidovudine and nevirapine; antimalarial combinations of artemether and lumefantrine; as well TB drugs rifampin, isoniazid, pyrazinamide and ethambutol hydrochloride.

Indian companies that have outsourced their clinical trials to Semler – those include Hyderabad-based Mylan Laboratories Ltd., part of Mylan NV, Mumbai-based Lupin Ltd. and Bangalore-based Strides Shasun Ltd. – may need to repeat studies for some of their products with a different CRO due to the FDA’s rejection of Semler’s data.

Strides Shasun’s chief financial officer, Badree Komandur, issued a statement, saying that “there will not be any impact on the company’s business as the two tuberculosis products mentioned in the notice of concern” pertaining to its institutional business “have been discontinued since mid-2014.”

The FDA letter said that it did not find reports that “raise serious safety concerns with products” that were approved based on data from Semler during its evaluation and review of postmarket adverse events for all drug.

The FDA is also changing the therapeutic equivalence rating for any approved ANDA that relied on data from Semler to “BX”. A BX rating indicates that data reviewed by the agency are insufficient to determine therapeutic equivalence.

Semler and the three companies mentioned in the WHO letter did not respond to BioWorld Asia’s queries.

The impact on the stock prices of some of the companies affected has been limited. Lupin’s stock price dropped from INR1572.6 (US$23.6) on April 20 when the FDA letter was posted to INR1561 the next day but bounced back to INR1576.3 on April 28. Strides Shasun’s stock price dropped from INR1124 on April 20 to INR1082 on April 28.

Erosion of trust

The latest case involving Semler is one in a growing list involving Indian pharmas that have been dogged by controversies of data integrity and the industry is now beginning to fear that such incidents are affecting brand India.

A report released in March 2016 on the evolving landscape of India’s health care industry noted that “quality violations and increased scrutiny by the U.S. FDA on manufacturing facilities of several Indian pharmaceutical majors [are] threatening to cause global erosion of trust in Indian drugs.”

“We [the Indian pharma industry] do have a quality problem,” said Aditya Berlia, member of the management board of the Apeejay Svaran Institute for Biosciences & Clinical Research, at a conference to mark the release of the report that was prepared by the Associated Chambers of Commerce and Industry of India and Hyderabad-based Sathguru Management Consultants.

Berlia had cautioned that if Indian companies did not gear up to meet the stringent FDA standards, “50 to 70 percent of pharma firms in India will need to be shut down.”

Earlier in 2015, Krishna Ella, managing director of Hyderabad-based Bharat Biotech International Ltd., said a key problem is Indian firms’ reluctance to verify whether new recruits had previous track records of poor data quality maintenance in their previous organizations.

An Ernst & Young survey in 2015 also highlighted serious issues of lax documentation, absence of data reviews, and severe work pressures to demonstrate key performance indicators of products. (See BioWorld Today, July 15, 2015.)