Asia Regulatory Roundup: India Sets Guidelines for Fixed-Dose Combination Trials (13 June 2017)

Regulatory NewsRegulatory News | 13 June 2017 |  By 

Welcome to our Asia Regulatory Roundup, our weekly overview of the top regulatory news in Asia.

DCGI Sets Guidelines for FDC Trials as Long Wait for Phase IV Protocols Continues

The Drug Controller General of India (DCGI) has outlined how makers of fixed-dose combinations (FDCs) can meet regulatory demands for clinical data on their drugs. DCGI Dr. GN Singh is asking FDC manufacturers to focus on safety data and is providing flexibility in the design of clinical trials in a bid to overcome long-standing resistance from the industry.

Singh and his colleagues have spent more than four years trying to get manufacturers of FDCs to provide data to show the safety and efficacy of their products. Manufacturers were originally given 18 months to provide data on products that came to market without the approval of DCGI. Only a minority of companies met that deadline, forcing Singh to reiterate his demand for manufacturers to submit Phase IV clinical trial protocols last year. That plea was as unsuccessful as earlier calls for data and post-marketing trial protocols.

Faced with the continuing failure of FDC manufacturers to comply with the request, Singh tasked an expert committee with considering how to get more companies to submit Phase IV protocols. The committee has responded with a series of recommendations.

Noting that many of the FDCs for which Phase IV protocols are needed appear to be rational, the committee recommended narrowing the focus of the requested trials. The committee wants trials to primarily gather data on the safety of the FDCs. Efficacy is relegated to a secondary objective. Earlier requests by DCGI demanded data on safety and efficacy. In narrowing the focus of the trials, DCGI has potentially reduced the burden of running the studies on FDC manufacturers and cut the likelihood they will fail to generate the required data.

DCGI, following the recommendations of the expert committee, has provided advice on how FDC manufacturers can design trials to generate the necessary data. The advice gives manufacturers lots of flexibility. Singh said the trials can be open label, double blind, comparative, single arm or crossover studies. Manufacturers should size the study to ensure statistical significance.

The committee and Singh were more prescriptive in other regards. Singh asked sponsors to ensure their trials use geographically distributed study sites. The recommendations also call for sponsors to clearly define the “anticipated safety parameter” and related monitoring mechanism.

Singh asked FDC manufacturers to submit Phase IV protocols that take the guidance into account.

In a separate notice sent on the same day as the trial protocol advice, Singh clarified the pathway for FDCs that are classed as rational but lack no-objection certificates. Singh moved to create a regulatory pathway for such FDCs in March, but the notice to unveil the plan lacked enough details for some manufacturers. Faced with questions about what documentation is needed, Singh has sent a memo listing what information manufacturers must provide to obtain a certificate. 

DCGI Notice, More

Further Evidence of Medicine Tampering in Australia Prompts Expansion of Recall

The Therapeutic Goods Administration (TGA) of Australia has received more evidence of medicine tampering. Arrow Pharmaceuticals and Novartis’ Sandoz are the latest companies to be affected by the switching of one drug into the packs of another, resulting in an expansion of the ongoing recall.

Arrow is recalling all batches of Valpam 5 5 mg tablets sold in 50-pill blister packs. The company took the action after learning some packs of Valpam 5 contain blister sheets of Sandoz’s blood pressure drug amlodipine. Sandoz is recalling one batch of amlodipine because some packs are missing a blister sheet, possibly because someone has substituted them into packs of Valpam 5.

The tampering is reminiscent of the situation that prompted Roche and Apotex to recall medicines from Australia last month. In that case, packs of Roche’s Valium — which contains the same active ingredient as Valpam — were recalled after blister sheets containing other medicines were found in some packs. Apotex recalled one batch of three products after learning some packages were missing a blister sheet. 

TGA has maintained its position on the likely breadth of the tampering in the face of new evidence of wrongdoing. The regulator believes the tampering is not widespread, the same position it took after reviewing the Roche case. TGA and other authorities are investigating the tampering cases and advising patients and healthcare professionals to be aware of the problem.

The evidence of tampering has revived memories of cases that hit Australia 17 years ago. Back then, criminals tried to blackmail Herron Pharmaceuticals and SmithKline Beecham by switching other medicines into packs of paracetamol. TGA established anti-tampering guidance in response to the events.

TGA Notice, More

Indian Vaccine Testing Program Undermined by Inadequate Information Gathering

The head of India’s Central Drugs Laboratory (CDL) has written to his counterpart at DCGI to get regulatory officials at ports to support his vaccine testing initiative. CDL chief Arun Bhardwaj wrote the letter after learning officials are failing to provide information his vaccine testing team needs.

Bhardwaj wants port officials to provide details of the number of batches imported and a copy of the release certificate from the country of origin. CDL will not issue a lot release certificate unless the manufacturer has imported all of the batch and the import quantity is mentioned in the filed documents. Currently, CDL is learning it is missing the documents it needs when it tries to update its records.

DCGI Singh responded to the letter by forwarding it to all the Central Drugs Standard Control Organization’s (CDSCO) port offices. Singh requested “strict compliance” with the requirements in a note to accompany the forwarded letter.

CDL performs lot release for all vaccines imported into India and manufactured locally from its laboratory in the town of Kasauli.  


CFDA Posts Guidance on Evaluation of Quality and Efficacy of Generic Drugs

China Food and Drug Administration (CFDA) has posted a clutch of draft generic drug guidance documents. The guidelines form part of CFDA’s ongoing attempt to raise the standards of generic drugs manufactured and sold in China.

CFDA has used the latest batch of six documents to expand the official list of reference products. The list now includes products found in the United States Food and Drug Administration’s Orange Book and equivalent texts managed by authorities in Europe and Japan. Generic drugmakers can acquire reference products from these overseas territories for use in their equivalence tests.

The draft guidelines cover where such tests should take place. CFDA expects companies to use certified clinical trial facilities.

China’s regulator also used the documents to outline the process and timelines companies follow when seeking its clearance to sell products. The texts cover the potential for CFDA to inspect the operations of companies seeking approvals.

CFDA is accepting feedback on the draft documents until 9 July.

CFDA Notice, More (both Chinese)

Other News:

TGA has urged healthcare professionals working in intensive care environments to report problems with their ventilators. The agency issued the notice after learning of a range of problems with the devices, including unresponsive touchscreens, spontaneous shutdowns and oxygen sensor malfunctions. Despite these problems, TGA is yet to hear reports of deaths associated with malfunctioning devices. The regulator suspects this may be because highly trained personnel were not present when the incidents occurred. TGA Alert



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