Notification to Pharmaceutical Companies:
Clinical and Bioanalytical Studies Conducted by Semler Research are Unacceptable
[4/20/2016] FDA is notifying sponsors of New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) that clinical and bioanalytical studies conducted by Semler Research Private Limited (Semler) located in Bangalore, India, are not acceptable as a result of data integrity concerns, and need to be repeated. Semler is a contract research organization that conducts bioequivalence and bioavailability studies for a number of pharmaceutical companies.
FDA is taking this action as a result of an inspection of Semler’s bioanalytical facility in Bangalore, India, conducted between September 29, 2015, and October 9, 2015. The inspection found significant instances of misconduct and violations of federal regulations, including the substitution and manipulation of study subject samples. Yesterday, FDA issued an “Untitled Letter” to Semler detailing our findings related to the facility. A copy of this letter is available below.
FDA has evaluated drugs that were approved based on data from Semler that supported approval during the regulatory review process. FDA has conducted a thorough review of postmarket serious adverse events for all drug products which had studies conducted at Semler facilities. To date, the agency has not identified reports that raise serious safety concerns with these products. However, FDA is requiring that sponsors of approved applications repeat the bioequivalence/bioavailability studies using an entity other than Semler. FDA is also changing the therapeutic equivalence (TE) rating in FDA’s Approved Drug Product with Therapeutic Equivalence Evaluations (the Orange Book) 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, i.e., substitutability, of the generic product to the drug it references.
FDA is sending letters to sponsors of applications that are currently under review that include data from studies
conducted at Semler. The letter informs the sponsor that it must repeat the bioequivalence/bioavailability studies using
an entity other than Semler at an acceptable alternate study site.
Affected sponsors are encouraged to review the documents below, and contact the relevant FDA review division in the Office of Generic Drugs or the Office of New Drugs for further information.
Sample Information Request to Sponsors
483: Semler Bangalore, India, issued 10/09/15
Semler Untitled Letter
EMA recommends suspension of medicines over flawed studies at
Semler Research Centre
Bioequivalence studies performed at the site cannot be used to support medicines approval in the EU
The European Medicines Agency (EMA) has recommended suspending a number of nationally approved medicines for which bioequivalence studies were conducted at Semler Research Centre Private Ltd, Bangalore, India. The Agency has also recommended that medicines currently being evaluated for authorisation and which rely only on bioequivalence studies from this site should not be authorised until bioequivalence is demonstrated using alternative data. Bioequivalence studies usually form the basis for approval of generic medicines.
The list of medicines recommended for suspension can be found here.
EMA’s review followed an FDA inspection (1) that identified several issues at Semler’s bioanalytical site, including the substitution and manipulation of subjects’ clinical samples. The World Health Organization (WHO) also raised serious concerns (2) regarding data integrity and manipulation of study samples following its own inspections of Semler’s bioanalytical and clinical sites.
The findings from FDA and WHO inspections call into question the quality management system in place at Semler, and thus on the reliability of the data of all bioequivalence studies, including those used to support marketing authorisation applications in the EU. EMA’s Committee for Medicinal Products for Human Use (CHMP) has concluded that the studies conducted at Semler cannot be accepted
in marketing authorisation applications in the EU. Thus, no medicines can be approved on the basis of these studies.
During the evaluation, alternative studies were provided for some of these medicines. These studies show bioequivalence, and therefore, the CHMP has recommended that these medicines can remain on the market. The list of medicines recommended to remain on the market can be found here.
Some of the medicines which have been recommended for suspension may be of critical importance (e.g. due to lack of available alternatives) in a given EU Member State. Therefore national authorities can temporarily postpone the suspension in the interest of patients. Member States should also decide whether recalls of the affected medicines are needed in their territories.
The CHMP’s recommendation concerning these medicines will now be sent to the European Commission
for a legally binding decision valid throughout the EU.
Information for patients and healthcare professionals
• A number of medicines for use in the EU rely on studies carried out at the Semler site in India.
The studies, called ‘bioequivalence’ studies, are usually the basis for approving generic
• The bioequivalence studies performed at the Semler site have been found to be flawed, so they
cannot be relied on. As a result, several medicines approved in the EU are being suspended.
• The list of medicines recommended for suspension can be found here.
• National authorities in the EU will consider how critical individual medicines are in their
countries and make final decisions on whether to suspend or allow them to remain available, while
new data are generated.
• There is currently no evidence of unexpected harm or lack of effectiveness with any medicine
approved on the basis of studies conducted at Semler.
• Generic medicines containing abacavir/lamivudine (used to treat HIV), which were approved on the
basis of studies conducted at Semler, can remain on the market in the EU. This is because during
this review, alternative studies from different sources were provided that show bioequivalence.
• Medicines still under evaluation cannot be granted authorisation in the EU on the basis of
studies conducted at Semler; further data would have to be provided to support authorisation.
• Medicines to be suspended can have their suspension lifted if the companies provide alternative
data demonstrating bioequivalence.
• Patients should continue to take their medicines as prescribed and contact their doctors in case
of questions or concerns.
More about the medicines covered by this review
The review covers medicines authorised via national procedures in individual EU Member States, whose marketing authorisation applications included data from Semler’s bioanalytical site (Semler Research Center Private Ltd, 75A, 15th Cross, 1st Phase, JP Nagar, Bangalore 560 078, Karnataka, India) and from Semler’s clinical site (PA Arcade, #21, 22, 23, Kodigehali Main Road, Sahakaranagar Post, Bangalore 560 092, Karnataka, India).
It also includes ongoing marketing authorisation applications for medicines which use study data from these sites. No generic medicine authorised centrally via EMA was tested in these sites.
More about Semler
Semler is a contract research organisation (CRO) with an analytical and a clinical site located in Bangalore, India. These sites conduct the analytical and clinical parts of bioequivalence studies, some of which are used to support marketing authorisation applications of medicines in the EU. The Semler site also performs bioequivalence studies for some medicines authorised in the US and medicines included in the WHO prequalification programme.
More about the procedure
The review of Semler was initiated on 28 April 2016 at the request of Denmark, Germany, the Netherlands, Spain and the United Kingdom under Article 31 of Directive 2001/83/EC. The review has been carried out by the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which has adopted the Agency’s opinion. The CHMP opinion will now be forwarded to the European Commission, which will issue a final legally binding decision applicable in all EU Member States. The CHMP opinion allows for national authorities to take decisions on how critical individual medicines are in their countries.