Pharmacovigilance inspections

The safety of drugs is of paramount importance to patients and healthcare professionals. The pharmaceutical industry has an ethical and legal responsibility to ensure that the products they sell will not harm the patients they are intended for. The repercussions of a new drug having a potentially serious side-effect profile are enormous for patients, healthcare professionals and the industry.

There have been many drugs that were very successful and benefited thousands of patients, but were later found to have serious side-effects, resulting in their withdrawal. The most notable recent example was Vioxx, launched in 1999 and withdrawn in 2004 with total sales of $2.5 billion from 100 million prescriptions issued. The cost to Merck in terms of loss of revenue, personal injury lawsuits and reputation has been significant. There is also the impact on the class of drugs, with an increase in the level of testing required for all COX 2 inhibitors in development, and monitoring of safety when on the market.

The regulatory bodies that approve licenses have a responsibility to protect the public; in the mission statement of the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom, it states that their remit is to “enhance and safeguard the health of the public by ensuring that medicines work and are safe.”

The US Food and Drug Administration (FDA) in the United States has been severely criticized for not acting on information regarding heart attacks and stroke from healthcare professionals prescribing Vioxx. As a result, the FDA has established an independent Drug Safety Oversight Board in 2005 to oversee the management of drug safety issues. In addition, it has issued guidance for industry on good pharmacovigilance practices and pharmacoepidemiologic assessment (March 2005).[1] The guidance includes the requirement for routine risk management and risk minimization activities to be conducted by the industry.

Public pressure on industry and regulatory bodies to improve the monitoring of drug safety has led to greater scrutiny of the groups responsible within organizations, namely the pharmacovigilance departments. Regulatory bodies do not have the resources to closely monitor the safety of all drugs that are licensed in their regions, and rely on the industry to do this. To ensure that the industry is meeting its legal responsibilities, the level of pharmacovigilance inspections by European regulatory authorities has significantly increased. Many European authorities such as those in the United Kingdom, France, Germany and Sweden conduct regular inspections of sponsor organizations′ pharmacovigilance activities. In addition to the pharmacovigilance inspections, the inspectorates conduct good clinical practice inspections, which include a pharmacovigilance component relating to clinical trials.

The focus of most European pharmacovigilance inspections is on the systems and processes in place to monitor drug safety, for products in pre- and post-marketing stages. However, product-specific inspections may take place if there are concerns about safety, or the effectiveness of monitoring safety by the license holder. All inspections are resource intensive and require significant planning and preparation by the inspectees to ensure a positive outcome.

Marketing authorization holders (MAHs), or companies with an approved clinical trial application (CTA) in place may be subject to inspection at any time. Most inspectorates apply a risk assessment model to target limited resources at the highest risk areas. In the United Kingdom, the MHRA planned to conduct inspections of all MAHs every 3 years, but because of the large number of drugs licensed in the United Kingdom, they have had to adopt a risk assessment strategy. Companies are selected on the basis of several criteria, such as not providing details of the qualified person for pharmacovigilance (QPPV) to the MHRA, companies with new products on the market, products with a known safety risk, poor compliance history, or non-compliance with 15-day reporting.

Statutory inspections may be notified to the MAH in advance (usually 1-3 months in Europe), or they may be given virtually no notice if there is a valid reason for a ‘triggered’ or ‘for cause’ inspection. The notification letter will include a request for documentation describing the pharmacovigilance quality system, both nationally and globally (if a global company). The MHRA requires sponsor companies to complete a specific document called the ‘Summary of Pharmacovigilance Systems’ or SPS.[3] This document requires the contact details of key pharmacovigilance personnel, both in the United Kingdom and at the company headquarters (if not UK), including the QPPV; the number of licenses in place in the United Kingdom; the company structure and operating model for pharmacovigilance; the pharmacovigilance system (responsibilities of the UK department and interface with other functions); computer systems used; quality systems in place and archiving arrangements. Several appendices should be attached to provide further detailed information such as all organization charts; full product portfolio; details of clinical studies; list of SOPs; compliance statistics; third party agreements in place; and product-related safety issues. The time taken to compile this information can be quite extensive.

Once the inspection team have reviewed all of the documents sent to them, they prepare an ‘Inspection Plan’, which is essentially an agenda indicating which functions will be interviewed and when. The company has an opportunity to comment on the Inspection Plan to ensure that they can get the right people in the right place at the right time. The Inspection Plan will include interviews with non-pharmacovigilance personnel such as Medical Affairs, Regulatory Affairs, Sales and Marketing and Clinical Operations. Companies must ensure that all affected personnel are aware of the inspection and make themselves available.

The number of inspectors and the duration of the inspection are dependent on the size of the company's product portfolio. The inspection team may consist of two inspectors spending 2 days at the company, or up to four inspectors for more than a week. Inspectors may want to conduct interviews in parallel to maximize the time available, so companies must be prepared to find appropriate facilities to accommodate the inspection interviews.

Unless it is a focused inspection, inspectors will test all aspects of the pharmacovigilance system. In Europe, the QPPV has a pivotal role and is legally responsible for all pharmacovigilance activities within Europe for marketed drugs. The QPPV must be continuously and permanently available, and the inspectors will test the out-of-hours systems before the inspection to ensure that they are meeting their legal responsibilities. The level of oversight by the QPPV will be scrutinized including their input into risk management plans and post-authorization safety study protocols. The Deputy QPPV will also be interviewed to establish how well-informed they are about the pharmacovigilance system and current drug safety issues.

The UK's MHRA has started publishing statistics on the number of pharmacovigilance inspections conducted every 6 months, and the types and frequency of findings[2] (www.mhra.gov.uk). The MHRA conducted 75 pharmacovigilance inspections in the United Kingdom in 2006, including 11 re-inspections. The types of organizations inspected were innovative pharmaceutical companies, generic manufacturers and organizations described as ‘other’. From these inspections, there were 41 critical findings, 221 major findings and 285 other findings. All inspections with critical findings are referred to the ‘Inspection Action Group’ in the United Kingdom, which is a non-statutory, multi-disciplinary group that advises on an enforcement action. The types of recommendations that they can make include re-inspection, sharing of information with other authorities where applications may be in progress, sending a warning letter, or meeting with the MAH representatives. One case to date has been referred to enforcement for criminal prosecution.

The analysis of the inspections in 2006 highlighted key areas where critical findings were made; this included overall failure of the pharmacovigilance system, spontaneous case processing, production of periodic safety update reports (PSURs) and the role and responsibilities of the QPPV. Other areas frequently identified as critical findings were signal generation, contracts and agreements with third parties and clinical trial case processing.

The major findings included all areas of pharmacovigilance activity, but the highest numbers of findings were related to the spontaneous case reporting, the QPPV, PSUR production, quality assurance activities and signal generation.

The MHRA conducted a survey of companies who have been inspected to determine their level of satisfaction with the process.[4] Nineteen companies participated and they were asked to score their level of satisfaction across the five phases of the inspection process, namely, pre-inspection activities; the opening meeting; conduct of the inspection; the closing meeting and the inspection report. An overall question asking whether the company felt that they had benefited from the inspection was also asked.

The overall percentage satisfaction rate was 90% (80-97%). Less than 2% of the scores were in the ‘dissatisfied’ category and none was in the ‘totally dissatisfied’ category. The dissatisfaction reported mainly concerned the completion of the SPS. The MHRA has considered that the format and use of the SPS may need to be reviewed.

So what do companies need to do to avoid critical and major findings at inspection? First, every MAH or CTA holder that undertakes pharmacovigilance activities must have a good quality system in place. Standard operating procedures (SOPs) must be compliant with current regulations and accurately describe pharmacovigilance activities. Staff must be trained in their SOPs, and this should be confirmed by written evidence. Staff must keep their training records, CVs and job descriptions up to date. The SOPs should be effective on a global basis (if a global company), but there should also be local procedures to ensure that all activities are appropriately documented.

Staff within the pharmacovigilance department must be trained, not just in the SOPs, but also on the regulations that apply to pharmacovigilance. This is to ensure that they understand their legal responsibilities and appreciate the significance of what they are doing. The QPPV must be very clear on their responsibilities, and these should also be documented in policies and procedures. Senior management should be seen to be providing the necessary support and resource to the QPPV to be able to perform their role in accordance with the legal requirements. Out-of-hours systems should be tested on a regular basis to ensure that the QPPV or delegate can be contacted. Ensure that all pharmacovigilance staff know when the QPPV is not available and who their deputy or delegate is.

Computerized systems for the collection and tracking of serious adverse reactions must be validated, and there must be documented evidence of this. There must be procedures in place for reconciliation between multiple systems. There should be monitoring tools for individual case safety report and PSUR submission metrics. Any corrective and preventative actions for addressing poor submission metrics should be documented and followed-up.

Companies should ensure that pharmacovigilance departments are audited on a regular basis; this is not only a regulatory requirement, but is also useful in identifying any areas that could be a regulatory risk. Exposure to interviews by auditors is also good preparation for inspections, as is understanding and responding to audit findings. Companies should also consider conducting ‘mock inspections’ at intervals to test their ‘inspection readiness’.

As discussed previously, the penalties for non-compliance can be quite severe. Most agencies allow companies to correct deficiencies and then re-inspect to confirm that appropriate corrective action has been taken. However, if the deficiencies are considered to be so serious that patients could be at risk, the authorities can suspend a license or CTA, which could have a significant impact on the company's revenue and reputation. In the scheme of things, the cost of implementing and maintaining an effective pharmacovigilance quality system is insignificant in comparison.