Asia Regulatory Roundup: Gilead Warns TGA Could ‘Drastically Expand’ Use of Boxed Warnings

Regulatory NewsRegulatory News | 30 October 2018 |  By 

Welcome to our Asia Regulatory Roundup, our weekly overview of the top regulatory news in Asia.
Gilead Warns TGA Guidance CouldDrastically Expand’ Use of Boxed Warnings
Gilead Sciences has criticized the Therapeutic Goods Administration’s (TGA) draft guidance on boxed warnings. The biotech warned the proposal could “drastically expand” use of the safety alerts and thereby limit their effectiveness.
Australia passed a resolution covering boxed warnings in the mid-1990s. The idea was to create a way to highlight certain particularly important adverse drug reactions in the product information. Adverse events could be highlighted if they were life-threatening, serious or unexpected. TGA continues to make use of the mechanism — more than 30 products currently carry boxed warnings — but has not recently provided formal guidance on its application.
The agency set out to address the lack of formal advice in August with the release of a draft guidance document for consultation. The document provoked some strong negative reactions, although not all large biopharma companies objected to the proposals.
Gilead was among the dissenting voices. As Gilead sees it, the guidance could lead to boxed warnings being used to highlight adverse events that are neither life-threatening, serious nor unexpected. If that happens, the impact of the warnings may wane.  
“There is a significant risk that wider use of boxed warnings to less significant issues will lead to a dilution of the effectiveness this type of warning, a warning whose effectiveness is based largely on being unusual and highly prominent at the start of the [product information],” Gilead wrote in its feedback to TGA.
Gilead is particularly concerned about the application of boxed warnings in response to concerns about a class effect. If applied in this way, all products with a particular mechanism of action could be subject to boxed warnings because of adverse events linked to some members of the class. Gilead wants to limit the use of boxed warnings to cases when there is direct evidence a product causes an adverse event.
Bristol-Myers Squibb voiced similar concerns, noting that the criteria for requiring a boxed warning are “ill defined” and could be interpreted inconsistently. The upshot is Bristol-Myers fears the draft guidance could lead to the proliferation of boxed warnings.
Gilead and Bristol-Myers have significant concerns with the guidance, but are broadly supportive of TGA’s desire to clarify its position. However, Medicines Australia objected to the draft guidance on more fundamental grounds. The big pharma trade group argued against the need for a standalone guidance document on boxed warnings on the grounds that the use of the mechanism should be considered alongside other risk mitigation measures.
AbbVie and GlaxoSmithKline are members of Medicines Australia but provided notably more positive feedback to TGA. Both companies support the introduction of boxed warning guidance and, while they have issues with some details, wrote feedback that sounds less alarmed than the submissions from Bristol-Myers and Gilead. AbbVie, for example, brought up an issue with the removal of boxed warnings based on class effects but did not object to the use of the alerts in this context.
It is unclear how TGA will respond to the mixed feedback. While TGA sometimes responds to feedback when it publishes the submissions, on this occasion it is still considering what actions to take. TGA is due to publish details of the outcome of the consultation in November. 
Consultation Submissions
TGA Outlines ‘Pragmatic Approach’ to Enforcement of new Advertising Code
TGA has outlined the “pragmatic approach” it plans to take after the 2018 advertising code comes into effect. The clarification comes weeks after TGA rejected industry calls to extend the transition period and thereby give companies more time to make their advertisements compliant with the new rules.
In the earlier release affirming its plans to implement the code in the new year, TGA said it would take a more lenient approach to enforcement over the first six months of 2019. The release sought to allay fears that TGA would take a hard-line approach against companies that failed to adapt to the new requirements regarding mandatory statements by the implementation deadline.
Now, TGA has published another statement designed to further dispel those concerns. The latest publication fleshes out the model TGA put forward when it affirmed the 2019 implementation date. The fleshed-out enforcement model is guided by the risk advertisements pose to public health and safety.
“Where an advertiser publishes an ad that is not compliant with the 2018 Code, but would have been compliant with the 2015 Code, in particular in relation to requirements such as the mandatory statement used, scientific citations and testimonial disclosures, this is unlikely to pose a significant risk to public health,” TGA wrote.
If TGA receives complaints related to these requirements over the first six months of 2019, it is unlikely to do more than remind the offender of their obligations under the new code. In the second half of 2019, TGA will ask for information about the process being followed to correct the advert and the dates of related milestones before deciding whether to take further action.
TGA published details of its planned approach to enforcement in response to industry requests for information. Companies, particularly large organizations with lengthy internal approval processes, are worried that they will be unable to make all their ads compliant with the incoming rules by January.
TGA Statement
India Flip-Flops on Changes to Reporting of Adverse Events in Clinical Trials
India has proposed and quickly dropped changes to the reporting of adverse events in clinical trials. The Central Drugs Standard Control Organization (CDSCO) stated it would limit the type of reports that could be sent to one of its units, only to change its mind days later.
CDSCO published the first notice on 25 October. The notice stated the serious adverse event division at Sadiq Nagar, New Delhi would only accept reports of side effects involving drugs being tested in India. The change would have stopped organizations from using Sadiq Nagar to report adverse events related to the use of marketed drugs in a range of contexts.
However, CDSCO published a second statement on 29 October. The notice stated the prior change was on hold until further notice. CDSCO provided no explanation for the U-turn.
CDSCO Notice
TGA Sets 2020 Deadline for Industry-Wide Transition to eCTD Submissions
TGA is planning to give the industry until July 2020 to switch to the electronic common technical document (eCTD). The phased transition to the harmonized electronic system is due to start in the first quarter of next year.
Today, TGA accepts submissions in the eCTD and non-eCTD electronic submission (NeeS) formats. NeeS was designed to ease the transition from paper to electronic submissions. As sponsors are now comfortable with electronic submissions, TGA wants to move fully to eCTD. The format has additional features and, according to TGA, is associated with a far lower rate of validation failures.
Ninety-five percent of new drug and biosimilar applications already use the eCTD format. Given the high rate of adoption, TGA plans to make the format mandatory in this context in the first quarter of next year. In contrast, 41% of minor variations and comparable submissions use eCTD, leading TGA to give companies until July 2020 to use the format in this context.
TGA is accepting feedback on the proposals until 4 December.
Draft Guidance


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