Semler - referral

Current status

European Commission final decision

Overview

 

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

On 21 July 2016, the European Medicines Agency (EMA) recommended suspending a number of nationally approved medicines for which bioequivalence studies were conducted at Semler Research Centre Private Ltd, Bangalore, India. The Agency also recommended that medicines 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 Semler - Marketing authorisations which are recommended for suspension and marketing authorisation applications which do not satisfy the criteria for authorisation as adopted by the CHMP on 21 July 2016 is available.

EMA's review followed an FDA inspection¹ 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 concerns² 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 called into question the quality management system in place at Semler, and thus 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) 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 recommended that these medicines can remain on the market. The Semler - Marketing authorisations which are recommended for maintenance and marketing authorisation applications for which bioequivalence vis-à -vis the EU reference medicinal product has been established as adopted by t... is available.

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 was sent to the European Commission for a legally binding decision valid throughout the EU.

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¹FDA notification to Pharmaceutical Companies: Clinical and Bioanalytical Studies Conducted by Semler Research Are Unacceptable.

²WHO pre-qualification team - Inspections Services - Notice of concern.

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 medicines.
• 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 have been suspended.
• The Semler - Marketing authorisations which are recommended for suspension and marketing authorisation applications which do not satisfy the criteria for authorisation as adopted by the CHMP on 21 July 2016.
• 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 that have been 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 covered 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, 15^th Cross, 1^st 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 included 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 was 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 was forwarded to the European Commission, which issued a final legally binding decision applicable in all EU Member States on 22 September 2016.

Semler Article-31 referral – EMA recommends suspension of medicines over flawed studies at Semler Research Centre

Reference Number: EMA/489380/2016 Summary:

Bioequivalence studies performed at the site cannot be used to support medicines approval in the EU

Key facts

About this medicine

• Approved name:
  Semler

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/1443
• Type:
  Article 31 referrals

  This type of referral is triggered when the interest of the Union is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

Key dates and outcomes

• CHMP opinion date:
  21/07/2016
• EC decision date:
  22/09/2016

All documents

Procedure started

Semler Article-31 referral – Annex IA and IB

Reference Number: EMA/314147/2016 Corr. 6

Opinion provided by Committee for Medicinal Products for human Use

Semler Article-31 referral – Review started

Semler Article-31 referral – CHMP list of questions

Adopted

Semler Article-31 referral – CHMP list of questions to Semler research centre

Adopted

Semler Article-31 referral – Timetable for the procedure

Semler Article-31 referral – Notification

Semler Article-31 referral – EMA recommends suspension of medicines over flawed studies at Semler Research Centre

Reference Number: EMA/489380/2016 Summary:

Bioequivalence studies performed at the site cannot be used to support medicines approval in the EU

European Commission final decision

Semler Article-31 referral – CHMP assessment report

Reference Number: EMA/633696/2016

Semler Article-31 referral – Annex II

Semler Article-31 referral – Annex III

Description of documents published

Please note that some of the listed documents apply only to certain procedures.

• Overview - lay-language summary of the stage of the procedure
• Notification – a letter from a Member State, the European Commission or the marketing authorisation holder requesting the initiation of the procedure
• Scientific background – further background information from the triggering Member State on the issues leading to the initiation of the procedure (if applicable)
• List of questions – questions agreed by the Committee requesting further information from the marketing authorisation holder(s) / applicant(s) to evaluate the issues identified
• Timetable for the procedure – agreed timeframe to respond to the list of questions, to assess the issues and to adopt a conclusion
• List of medicines concerned by the procedure – medicine(s) / active substance(s) concerned, and marketing authorisation holder(s) / applicant(s)
• List of questions to be addressed by the stakeholders – call for data to be submitted by stakeholders (e.g. healthcare professionals, patient organisations, individual patients) (if applicable)
• Stakeholder submission form – form to be used by stakeholders to submit data (if applicable)
• Scientific conclusions – scientific conclusions of the PRAC and/or CHMP and/or CMDh
• Assessment report – PRAC or CHMP assessment and conclusions on the issues investigated, including divergent positions (if applicable)
• Divergent positions – divergent positions of the CHMP or CMDh members for pharmacovigilance procedures (if applicable)
• Changes to the summary of product characteristics, labelling and package leaflet (amended sections or fully revised version) (if applicable)
• Condition(s) to the marketing authorisation(s) – condition(s) for the safe and effective use of the medicine(s) (if applicable)
• Condition for lifting the suspension – condition to be fulfilled for the suspension of the marketing authorisation(s) to be lifted (if applicable)
• Timetable for implementation of CMDh position – agreed timeframe to submit and finalise the variation(s) implementing the outcome of the procedure (if applicable)

Note that older documents may have different titles.