European Regulatory Roundup: EMA Issues Increasing Number of GMP Non-Compliance Statements in India (11 May 2017)

Posted 11 May 2017 By Nick Paul Taylor

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EU GMP Inspectors Issued Non-Compliance Statements to 11% of Indian Sites Visited in 2016

Authorities in the European Economic Area (EEA) issued non-compliance statements to 11% of the Indian drug manufacturing plants they inspected in 2016. The rate of non-compliance is far higher than the 1% recorded globally in 2016 and the 4-6% level seen in India in the three previous years.

In 2016, inspectors from the EEA performed good manufacturing practice (GMP) inspections at 108 facilities in India. These EEA inspections resulted in the issuance of 96 GMP certificates and 12 non-compliance statements, meaning more than one in every 10 plants inspected failed to meet regulatory standards. That makes India an outlier compared to both the GMP standards of other countries in 2016 and its own historic levels of compliance. 

Inspectors from EEA countries — the European Union member states plus Iceland, Liechtenstein and Norway — visited 2,293 manufacturing facilities last year. These visits led to 24 statements of non-compliance and a GMP failure rate of 1%. When India is removed from the analysis, the rate of non-compliance falls to 0.5%. The global rates of non-compliance in 2015, 2014 and 2013 were 0.65%, 0.63% and 1.1%, respectively.

The rate of non-compliance in India was above the global average in each of those years, but the gap grew notably in 2016. In 2015, 2014 and 2013 EEA GMP inspectors issued non-compliance statements to 4.3%, 4.6% and 6.3%, respectively, to the Indian manufacturing plants they assessed.

EEA inspectors have only once failed plants in a country like they did in India last year. In 2013, EEA inspectors issued non-compliance statements to eight of the 71 Chinese sites they visited, giving the country a GMP failure rate of 11%. Since then, the rate of non-compliance statements issued to Chinese manufacturers has ranged from 5.3% to 7.7%.

The European Medicines Agency (EMA) presented the data in its annual report but offered no explanation for why Indian sites fared particularly badly in GMP inspections last year. EMA did detail the consequences for the recipients of the seven statements of non-compliance it issued in relation to centrally authorized products. One firm was prohibited from supplying the affected medicine in the EU. Another two companies were blocked from supplying active pharmaceutical ingredients for non-critical medicines.

EMA’s overview of the outcomes of good clinical practice (GCP) inspections in 2016 presented a more favorable take on quality in India. That analysis grouped India in with the rest of the Middle East and Asia Pacific region. Sites in this area accounted for 16% of GCP inspections last year and were responsible for 3.5% of the critical deficiencies identified.

Annual Report

Rise of Experimental Anti-Influenza Candidates Prompts EMA to Propose Guideline

EMA is planning to create a guideline on the clinical evaluation of drugs to treat influenza. The guideline will fill a gap in EMA’s portfolio of regulatory advice that the emergence of a pipeline of experimental anti-influenza drugs has exposed.

Today, influenza is either treated with neuraminidase inhibitors such as GlaxoSmithKline’s Relenza and Roche’s Tamiflu or by M2 ion channel inhibitors. These drugs came to market without the help of dedicated guidance on the clinical evaluation of influenza medicines. Now, with requests for scientific advice on anti-influenza drugs increasing as R&D activity in the area grows, EMA wants to set down its position in a formal guideline.

The regulator has begun the process by releasing a draft concept paper. In the draft, EMA sets out its motivations for planning the guideline, the shortcomings with the data to support existing drugs and how these factors are influencing its thinking about the scope and detail of the planned text. Significant areas of trial design uncertainty remain, in part because Tamiflu — also known as oseltamivir — is widely used to treat severe influenza despite the lack of data on its efficacy.  

“The feasibility of randomizing patients to placebo treatment without any antiviral agent needs to be considered. Showing superiority over oseltamivir would convincingly demonstrate efficacy but given the unknown effect of oseltamivir in severe influenza, may be a high hurdle. Because the effect of oseltamivir over placebo is not well documented, constructing a [non-inferiority] margin that, if met, would establish evidence of efficacy, is problematic at this stage,” EMA wrote.

EMA’s Infectious Diseases Working Party plans to spend the rest of the year working out these and other issues with a view to publishing a draft guideline in the first quarter of 2018. The draft concept paper is open for comment until the end of July.

Draft Paper

EMA Starts Reworking Pediatric Pharmacokinetic Guideline in Light of 10 Years of Experience

EMA has begun the process of revising its guideline on the role of pharmacokinetics in developing drugs for pediatric patients. The revision will build on the scientific advances and accrual of regulatory experience that have happened since EMA introduced the original guideline in 2006.

Officials at EMA’s Pharmacokinetic Working party expect most of the changes to relate to the need to optimize study designs and the use of pharmacokinetic modeling methods.

In terms of study designs, EMA plans to reevaluate everything from its general recommendations on how to set up pediatric pharmacokinetic and pharmacodynamic studies to more specific points covering topics such as how and when to use individualized dosing through continuous titration. EMA will also look at how to use simulation-based approaches to optimize the design of studies.

The modeling revisions will include recommendations for analyses using either simple or complex models. EMA will also look at the use of prior pharmacokinetic and pharmacodynamic data and how to weight it properly against freshly generated data.

EMA is accepting comments on the draft concept paper until the end of July. The agency will then start work on a draft guideline, but it expects this to take it until the fourth quarter of 2018. Once ready, EMA will release the text for a six-month consultation period.

Draft Paper

PRAC Finds No Difference in Inhibitor Development Between Types of Factor VIII Medicines

EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has found no difference in inhibitor development between classes of factor VIII medicines. PRAC ran the review to assess differences between drugs derived from plasma and those made using recombinant DNA technology.

Data from a randomized-controlled trial published last year suggested plasma-derived factor VIII medicines were more likely to cause the development of inhibitors than recombinant DNA drugs. That prompted PRAC to look at the results of the trial and other studies to assess whether the risk of inhibitor development is actually greater for one class of product than the other.

PRAC found “no clear and consistent evidence” of such a difference. This lack of clear evidence may stem from differences in the design and patient populations used by the studies.

The findings of the review have prompted PRAC to change its focus. Rather than divide factor VIII drugs into two classes for analysis, PRAC plans to assess inhibitor development on a product by product basis. The committee will perform this product-focused analysis as more evidence on each drug becomes available.

PRAC’s current review has led to some recommendations. The recommendation calls for inhibitor development to be listed as a very common side effect in previously-untreated patients. 

PRAC Report

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Categories: Biologics and biotechnology, Drugs, Medical Devices, Regulatory strategy, Regulatory intelligence, News, Europe, EMA, EC

Tags: European regulatory roundup, PRAC, GMP inspections, flu vaccine guidance

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