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Posted 03 April 2019 | By Nick Paul Taylor
Welcome to our Asia Regulatory Roundup, our weekly overview of the top regulatory news in Asia.
India Drops Interim Compensation Requirements From Proposed Clinical Trial Rules
India has dropped interim compensation requirements from its clinical trial rules following feedback from industry. The previous draft of the rules required sponsors to make quick payments to research subjects if the ethics committee deemed a clinical trial to have caused death or permanent disability.
If the interim compensation clause had come into force, ethics committees would have responded to a death or permanent disability in a clinical trial by looking for a causal link to the study. When the committee found a causal link, it would give the study sponsor 15 days to pay the research subject or their legal heir 60% of the amount of compensation due under a formula discussed elsewhere in the rules.
In revising the draft rules, officials have dropped the interim compensation clause. The removal of the clause means compensation will only be paid after a more thorough analysis of whether a study caused the injury or death. In the case of deaths, the central licensing authority will task a committee with assessing the cause of death. The sponsor, investigator and ethics committee will all forward reports on the incident. A similar process exists for permanent disabilities.
The change means study subjects and their heirs will need to wait longer to receive compensation. However, the new process eliminates the risk that an ethics committee, acting without the support of the regulator, will misjudge the link between a serious adverse event and clinical trial and wrongly order a sponsor to pay compensation.
Other changes include the provision for exemptions to rules covering the need to run clinical trials in India. The draft stated sponsors need to run Phase III trials in India before being granted permission to sell the drug in the country. The revised version adds the caveat that this rule applies “unless otherwise exempted.”
The rules also retain many of the sponsor-friendly provisions of the prior draft. The rules give Indian regulators 90 days to process many applications, including requests for permission to run clinical trials. If the Central Drugs Standard Control Organization (CDSCO) hits the deadlines, it will provide sponsors with the sort of predictable, relatively short timelines for setting up clinical trials that they enjoy in other territories.
India is bringing in most of the changes immediately. The exception is a section covering ethics committees that is subject to a 180-day implementation period.
TGA Overhauls Guidance on Risk Management Plans for Medicines and Biologicals
Australia’s Therapeutic Goods Administration (TGA) has overhauled its guidance on risk management plans (RMPs) for medicines and biologicals. The guidance features significant changes to sections on the RMP format, updating RMPs, periodic safety update reports (PSURs) and other topics.
TGA brought version 3.1 of the guidance into force in November 2017. A revised version was released for a targeted external consultation one year ago, leading to the publication of version 3.3 this week.
The latest guidance is significantly different from version 3.1. In the preapproval section of the guide, TGA has added a section on RMPs for generics. Many of the RMP requirements for manufacturers of generics overlap with those of other companies, but there are some differences.
Notably, TGA wants generics companies to align their summaries of safety concerns with those of the manufacturers of the originator products. This will entail looking at sources such as the Australian Public Assessment Report and its European equivalent. TGA also expects generics manufacturers to consider whether their product introduces new safety concerns, such as the potential for medication errors arising from the use of a different administration device.
TGA has made major changes to its postapproval advice, too. Version 3.1 of the guidance touched on PSUR requirements and updating RMPs, but the revision goes into far more detail. The guidance now provides more information on when companies should update RMPs and the timeframes for doing so. TGA expects manufacturers to seek its agreement before “prematurely ceasing or significantly altering” additional risk minimization and pharmacovigilance.
Similarly, whereas version 3.1 merely states TGA has adopted European Union PSUR guidelines, the current guidance details when TGA will apply the need to submit PSURs as a condition of registration, explains how to file the reports and explains how it will monitor compliance with the requirements. TGA may suspend registrations if it discovers significant noncompliance with the requirements.
TGA Guidance, Submission Form
TGA Delays Enforcement of Pill Manufacturing Standards Following Industry Feedback
TGA has extended the transition period for its incoming standards for pill manufacturing. The rules will now come into force on 31 March 2021, around one year later than originally planned.
Australia left rules on pills out of its last set of oral drugs standards in response to declining use of the dosage form. Whereas tablets are made using compression, pills are producing using wet massing, piping and molding techniques. These techniques have fallen out of favor in modern drug manufacturing operations but remain in use in some fields, notably Traditional Chinese Medicine.
When TGA proposed reintroducing standards on pills late last year, it planned to give manufacturers until April 2020 to comply with the rules. However, after receiving feedback, TGA has decided to give companies two years to adapt their operations to the pill standard.
The consultation process has also persuaded TGA to give manufacturers of all oral dosage forms two years to comply with a section covering elemental impurities and residual solvents. TGA thinks the transition period is needed to ensure companies have the time to review and update their medicines’ manufacturing documentation.
There is no transition period for other aspects of the standard, as they are the same requirements as in the previous set of rules. Manufacturers can choose to move to alternative testing options offered by the new standards at any time.
The big change in the latest document, TGO 101, is the expansion beyond the British Pharmacopoeia. Under the previous document, TGO 78, manufacturers had to follow BP monographs whenever there was a suitable standard. In TGO 101, TGA recognizes BP and its equivalents in Europe and the United States as comparable default standards.
DCGI Adds Warning to Labels of SGLT2 Inhibitors to Reflect Risk of Infection
The Drug Controller General of India (DCGI) has told manufacturers of SGLT2 to add a warning to the labels of their products. DCGI took the action after analyzing the risk of infection associated with diabetes drugs sold by AstraZeneca, Boehringer Ingelheim and Johnson & Johnson.
In recent years, regulators around the world have analyzed links between the diabetes drugs and side effects including inflammation of the pancreas and serious genital infections. India responded to the reports and actions of its regulatory peers by asking a metabolism subject expert committee to look into the topic. The review led to recommendations that authorities gather data on Indian patients and closely monitor new developments involving the drugs.
Later, after analyzing more safety reports, the committee advised CDSCO to tell manufacturers to add a warning to their product label. The warning outlines cases of “rare but serious infection of the genitals,” known as necrotizing fasciitis of the perineum, associated with use of the SGLT2 inhibitors.
DCGI Eswara Reddy ordered regional offices of CDSCO to direct manufacturers to make the change.
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