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International Clinical Trials

Safety Warning

Pharmacovigilance (PV) has become of paramount importance to everyone in the medical world, including patients, healthcare providers, the pharmaceutical industry, regulators and payers. Failures in PV by any of these stakeholders place a large burden on the healthcare system – especially on patients – but can also lead to poor medical outcomes, increased costs and loss of trust in the healthcare system as a whole. Thus, in order to produce effective drugs, good patient outcomes and deliver healthcare in an efficient manner, all partners must play an active role in PV (1).

For pharma organisations to fulfil their role, they must first understand the effectiveness of their PV system and ensure compliance with regulations where their products are used. Company-initiated audits, both internal and external, can help with this procedure. In a similar manner, regulators carry out inspections – not only in the pharma industry – to ensure compliance with PV regulations. Given the heightened level of scrutiny that the healthcare system is now facing, regulatory assessments are an everyday reality. The findings from these investigations will be provided to the business in an FDA Form 483. Additionally, the FDA can issue warning letters (WLs) to pharma companies for PV problems of regulatory significance. It has been found that most WLs are delivered for violations in PV fundamentals, which can lead to non-compliance in areas such as adverse event reporting, written procedures and periodic adverse drug experience report (PADER) submissions (2,3).

To continually improve the quality of PV globally, it is necessary to understand and learn from failures identified through WLs from the FDA to pharma businesses in postmarketing PV.

WL Issuance

Inspections carried out by the FDA can result in them issuing WLs to persons or organisations for violations of regulatory significance, which may lead to serious consequences. Their WLs are characteristically informal and advisory. The ultimate aim of a WL is to establish voluntary compliance with the law and provide prior notice. WLs can, on the one hand, result in enforcement actions if the violations identified are not adequately corrected; however, a WL does not commit the FDA to take action. On the other hand, the FDA can take action without prior issuance of WLs. Corrective, preventative or promised actions by the company do not preclude the FDA from issuing a WL. Therefore, receiving one is a cause for real concern to organisations, as the identified violations can lead to significant enforcement actions by the government, negatively affecting PR and future regulatory interactions (2,3).

While FDA WLs are available in the public domain, the findings from inspections – the FDA Form 483 reports – are generally not. The WL library on their website covers a wide range of violations related to foods, tobacco products and promotions of pharmaceutical products; only a small fraction is PV-related. From 2005 to 2015, a total of 17 WLs concerning postmarketing PV violations were issued to pharma companies. All of these WLs followed FDA inspection with Form 483 delivered to the business; most WLs also contained comments regarding inadequate response to Form 483, as well as notes related to repeat findings (4).

Three of the 17 WLs were addressed to large organisations, while the other 14 were issued to smaller ones and generic manufacturers. 13 WLs were written as primary PV violations, three were focused on Good Manufacturing Practices – but also contained comments about PV – while one WL was dedicated to a new drug definition. The WLs were generally evenly distributed between 2005 to 2015, with most years having between none and two WLs issued (4,5).

The two most common findings by FDA inspectors identified in the WLs were review of adverse drug experience (ADE) and reporting requirements. The evaluation of ADEs was generally focused on failures in written procedures, while the violations in reporting requirements most often related to postmarketing 15 day ‘alert reports’ and subsequent follow-ups, as well as oversights in PADERs. Other common results included failures in record keeping and reporting ADEs on marketed drugs without approved non-disclosure agreements, reporting of ADEs from a product complaint and reporting requirements for annual reports (4,5).


Consequences of WLs fall into two general categories: regulatory actions and outcomes related to public disclosure of the WL. The former is usually associated with failure to correct the violations and can include recall, seizure of products, injunction, administrative detention, civil penalties and/or prosecution.

Additionally, a WL may negatively impact future regulatory activities, such as approvals. The latter can affect a company’s PR to such an extent that it may lead to a loss of trust from patients and healthcare professionals, a decline in the stock price and a negative perception of the PV group within the organisation (2,3).

How to Respond

Following an investigation, the violations that occurred are presented in Form 483 and discussed with senior management of the company. Form 483 is not an allinclusive list, but identifies the FDA inspector’s observations regarding regulations that have been violated. Unless agreements have been made between the organisation and the FDA, the business has 15 days to respond to the findings in Form 483; however, ongoing or promised actions in the companies’ response to Form 483 do not preclude the FDA from issuing a WL (3,6).

Good responses to Form 483 after an inspection are crucial. In most of the 17 WLs discussed, however, the FDA commented that they were inadequate. Successful replies should acknowledge the problems; address each of them separately; demonstrate an understanding of the problems; evaluate the impact; determine the causes; and, finally, describe corrective and preventative actions.

If an activity is likely to take months, it can be split into milestones; thus, providing the FDA with the company’s roadmap for corrective and preventative actions. This roadmap will offer further assurance to the FDA that the business has a realistic plan with intent to complete these actions. Additionally, if possible, it would be best to correct any problems in the 15 days following the issuance of Form 483 and notify the FDA in the 483 response. Organisations should add any evidence of actions in the response to FDA, such as a new or corrected standard operating procedure (SOP), missing protocol or updated software (3,6).

Compliance and Good Practices

The optimal approach to avoiding a WL is to clearly understand the effectiveness of your PV services – especially any operational aspects – by setting acceptable targets which meet or exceed the regulations, and ensuring appropriate monitoring is in place. This can be achieved with metrics that evaluate key PV activities and audits both internal and external; however, the monitoring data must be reviewed – ideally by a standing committee – and the results used to initiate corrective and preventative actions to amend any deviations from the acceptable targets.

It is vital that the mindset of organisations becomes more open and accepting of the importance of effective PV.

Safety is not just a PV activity, and everyone in the company should be involved – including those outside of the business, like vendors and distributors, for instance. The management has to understand the significance of PV and lead by example. By increasing employees’ awareness of safety, and creating an organised, transparent and predictable process, organisations can help the FDA to clearly see how safety is being handled (1).

Companies should ensure that PV departments are audited on a regular basis; this is not only a regulatory requirement, but is also useful in identifying any areas that could become a potential regulatory risk. Exposure to interviews by auditors is also a good preparation for inspections, as is understanding and responding to audit findings.

Preventive Action

Protecting patient safety is a large, but vital responsibility for pharma businesses, and implementing a highly effective PV system is the best way to avoid WLs. This could include a monitoring method, acceptable targets and a review committee. Ensuring there are no repeat findings and providing a good response to Form 483 also decreases the risk of WLs, and the serious consequences that would follow. While much of this may seem overwhelming and complex at first, companies can partner with PV service providers that can help to improve the structure and set-up of PV organisation, develop appropriate SOPs and processes, and guarantee inspection readiness to avoid WLs.

1. The importance of pharmacovigilance, Safety monitoring of medicinal products, WHO, 2002. Visit: medicinedocs/en/d/Js4893e 2. US FDA Regulatory Procedures Manual – 4-1 Warning Letters. Visit: regulatoryproceduresmanual/ucm176870.htm
3. Frestedt J, Warning Letters Reference Guide 2016, Barnett International, Needham, MA
4. Warning Letters, US FDA, 2016. Visit: drugs/guidancecomplianceregulatoryinformation/ enforcementactivitiesbyfda/ warninglettersandnoticeofviolationletter stopharmaceuticalcompanies/ucm432949.htm
5. CFR Title 21. Visit: cfcfr/cfrsearch.cfm
6. FDA Form 483 Frequently Asked Questions, US FDA, 2015. Visit: www.

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Dr Mitchell Gandelman has 20 years of pharma industry experience in PV, medical affairs and international clinical development. As Principal of Global Consultancy Services of Safety and Risk Management at Sciformix Corporation, Mitchell is responsible for planning and building the company’s consultancy services business. He received his MD from the University of Connecticut, a PhD in Chemistry from the University of Colorado, and a BS in Chemistry from Trinity College.
Dr Mitchell Gandelman
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