Over
700 commonly used generic medicines were
recommended for suspension by the European Medicines Agency (EMA) based on data
integrity concerns, over clinical studies conducted at GVK Biosciences in
Hyderabad, India.What
will be the global fallout of the European decision? The European decision has
impacted products from companies such as:Abbott Laboratories, Accord Healthcare (Intas), Actavis, Alembic, Apotex, Betapharm (Dr. Reddy’s), Brown & Burk UK, Fair Med Healthcare AG, Glenmark, Lupin, Micro Labs, Mylan, Orion Corporation, Ranbaxy, Ratiopharm, Sandoz, Sanofi-Aventis, Stada, Teva, Torrent, Wockhardt, Zydus… and many, many more.The
original recommendation of suspending
some of the medicines
made in January 2015, was an outcome of an inspection of GVK Biosciences’ site in Hyderabad (GVK BIO is a Clinical Research Organization-
CRO) by the
French medicines agency (ANSM) through the EMA. The EMA stated in their official release: “The
inspection revealed data manipulations of electrocardiograms (ECGs) during the
conduct of some studies of generic medicines, which appeared to have taken
place over a period of at least five years. Their systematic nature, the
extended period of time during which they took place and the number of members
of staff involved cast doubt on the integrity of the conduct of trials at the
site.” 1000 drugs reviewed// 700
rejectedWhile
over 1,000 pharmaceutical forms and strengths were reviewed at the GVK site,
over 300 of them had sufficient supporting data available from other sources.
As a result, these medicines were allowed to remain on the market in the EU.However, for the over 700 other medicines, the EMA after its second review, maintained its previous recommendation of January 2015, to suspend medicines, where no additional supporting data from other studies was available. Only one exception after that second review was spared from suspension, as the company was able to address the EMA’s concerns: it was Bivolet Nebivolol (5 mg tablets/ marketing authorisation holder: Neo Balkanika EOOD).While the agency noted that “there is no evidence of harm or
lack of effectiveness linked to the conduct of studies by GVK Biosciences at
Hyderabad. Some of these medicines may remain on the market” if they are of critical importance for patients. However, the recommendation
will now be sent to the European Commission for a legally binding decision,
which will apply to Member States regardless of the decision taken in the
interim period.The updated list of medicines for which, the CHMP (Committee
for Medicinal Products for Human Use) recommends suspension, is available on the EMA website. Companies
are given 12 months to submit additional data. The potential global impact of the European
suspensions?The GVK Biosciences
scandal is almost as severe in magnitude and impact, as the data falsification
concerns, which were discovered at Ranbaxy (Katherine Eban’s stunning investigation in Fortune, “Dirty Medicine” covers this extensively). One of the main promoters of GVK Biosciences is Mr. D.S. Brar who was CEO & Managing Director of Ranbaxy from 1999-2004. The impact of GVK
Biosciences’ misdeeds is already being felt on new product launches. Mylan recently withdrew its European application for generic
Abilify (aripiprazole) (2014 sales US$6.2x billion) citing “identification of major GCP issues (Good
Clinical Practices).” What about the impact on the US market?In 2010, FDA discovered data integrity
violations, which bankrupted
clinical research organization, Cetero Research/PRACS. Based on the Cetero findings
in the United States, the EMA suspended seven drugs. Now it remains to
be seen, how the FDA will handle the data integrity concerns found in Europe
since products like repaglinide & candesartan cilexitil (Mylan), levetiracetam (Dr. Reddy’s), clonazepam (Sandoz), metformin hydrochloride (Actavis), tacrolimus (Panacea Biotech) all have U.S. FDA approvals. Leading GVK Biosciences’ defense is the Indian government, who warned last month that if the European Union does not reconsider their decision, it may go to the World Trade Organization. The Indian government’s position is based on an appeal by GVK Biosciences, which made the “Indian government set up a panel of experts last year to investigate
the matter and found no manipulation”, GVK Biosciences CEO Manni Kantipudi told Reuters.However, globally reputed GMP expert, Lachman Consultants, believes that the GVK Bioscience episode “could potentially impact data integrity, similar to the Cetero/PRACS
case”.It’s clear for us that this is not the end of the story…
Impressions: 4068
Dr. Reddy’s largest active pharmaceutical ingredient
(API) plant in Srikakulam (Andhra Pradesh, India) was inspected
by the USFDA in November, 2014. The Srikakulam facility received nine inspectional
observations and the company said, immediately after the inspection: “we will respond to the agency within stipulated timelines with our remedial plans and start implementing the necessary measures immediately”. The initial response indicated that the deficiencies at the Srikakulam plant were manageable.
However, and in
view of the recent USFDA import ban on the Ipca Laboratories’ facility in Pithampur (Madhya Pradesh - India), is it possible that Dr. Reddy’s Srikakulam facility could also be banned?
ENTER HEALTH CANADA
The basis on which the USFDA could potentially ban the Dr. Reddy’s Srikakulam plant, is that the facilities of both Ipca and Dr. Reddy’s were put under an import ban on December 23,
2014 by Health Canada citing concerns of data integrity at both sites.
Health Canada states in their release: “This action comes in light of recent
information from a trusted regulatory
partner that raises concerns about the reliability of the laboratory data generated at these sites.”
Health Canada
also lists the products impacted by the quarantine to be Domperidone, Valsartan, Capecitabine, Naratriptan and Desloratadine.
The
Naratriptan ban is noteworthy as Teva
& Sandoz, both who produce their product using Dr. Reddy’s API, are the only approved products on the Canadian market, and Naratriptan is now on the Canadian drug shortage list.
Following the
Canadian alert, the Ministry of Health in the United Arab Emirates, also decided to stop the importation and distribution of the products from Ipca’s Pithampur and Dr. Reddy’s Srikakulam sites.
US MARKET
The magnitude of the inspection was revealed by Dr. Reddy’s Co-Chairman & CEO, GV Prasad, when interviewed by the business channel CNBC in January.
He mentioned that the launch of both the generic Novartis’ Diovan (Valsartan - used to treat high blood
pressure and congestive heart failure) and AstraZeneca’s Nexium (Esomperazole
Magnesium – used to treat symptoms of conditions involving excessive stomach acid), would not occur unless the USFDA inspection report is
closed.
Almost immediately after the inspection, Dr. Reddy’s announced the possible shift of the manufacturing of some key products from Srikakulam;
including Esomperazole Magnesium.
Nexium sales
in 2014 were $3.6 billion and currently only Teva’s subsidiary, Ivax, has an approved generic on the U.S. market ; so Esomperazole Magnesium is definitely a strategic growth driver for Dr. Reddy.
In view of all the available information, the challenges confronting Dr. Reddy’s Srikakulam facility are immense. However, Dr. Reddy’s has overcome an import alert for their Mexican facility in the past, and hopefully, will be able to overcome
the problems at Srikakulam.
Also, a setback to Dr. Reddy’s, will further tarnish the image of the Indian pharmaceutical industry, which has had more than a dozen facilities receiving USFDA warning letters, because of data integrity concerns in the past two years.Click here to read the 9 observations at Dr. Reddy's Srikakulam API plant (source: Nomura).
Impressions: 11192
Update 2015 May 28:
Click here to see the orignal form 483 issued to Dr Reddy'sObservation 1Lab records don't include complete data derived from all tests. The inspectors indicate five instances where all the test failures were not documented and reported as per standard operating procedure (SOP). The reported results don’t contain the earlier sample analysis. Observation 2 The inspection highlights unauthorised access to computer
system. An instance was noted where data was deleted by an unauthorised person.
Observation 3 The Batch production and control records didn’t have the entries filled after each and every step as required by SOP. The data were filled simultaneously. Observation 4 Procedures regarding the issuance, revision, superseding
and withdrawal of documents not followed. Observation 5 Water used in the manufacture of APIs is not established
to be suitable for use. The microbiological test methods were not verified and
validated. Observation 6 Record of training of operators not maintained properly. Observation 7 Failure to justify and follow up on deviations or batch
failures: The inspectors made two observations where a batch has failed on
certain parameters. Either the investigations are incomplete or the conclusion
was not satisfactory. Observation 8 Process validations: The inspectors raised questions on
the process validation approach that would ensure that the process can be
performed effectively and reproduce the desired results. The inspectors
highlight a case of significant numbers of reprocessing carried out by the company,
raising questions on the process. Observation 9 Adequate and clean washing and toilet
facilities are not provided for personnel. The inspectors highlight that toilet
facilities are located at a long distance. Source: Nomura
Impressions: 5511