Pharmacovigilance: Playing by the Rules

The global pharmacovigilance scenario is changing both in terms of regulations and the efforts being undertaken by the regulators, pharmaceuticals industry, academia and healthcare professionals. Existing regulations are being revised and new regulations are being framed in several countries. However, gaps continue to exist as there is no harmonized regulatory approach and there are disparities in regulatory requirements that exist in many countries. Interestingly these gaps exist not only between the regulations of the developed and developing nations but also within the developed world.

The evolution of pharmacovigilance regulations in a particular country is dependent on several factors where the government plays a key decision-making role. The US, EU and Japan constitute the largest pharmaceutical markets and their regulations are some of the most stringent in the world. Elsewhere, the emerging markets are increasingly realizing the importance of pharmacovigilance and of constituting new regulations.

Differences in Approaches
Figure 1 illustrates the differences in the approaches taken by the pharmaceutical industry in the developing world compared to the industry in developed regions like the US, Canada and the EU. The approach taken by former can be termed as "Pharmacodiligence", represented by the triangle on the left, where the focus is on the collection of Adverse Drug Reaction (ADR) cases and reporting them within the expected timelines.

While companies invest in human and financial resources to comply with these regulations, there is minimal focus on performing risk-benefit evaluations on these cases. Such evaluations are perceived to be the responsibility of the innovator companies - almost all of which come from the developed world. The triangle on the right represents the approach taken by the industry in the developed regions, where the maximum effort is on risk management. This is the real purpose of pharmacovigilance, and pharmacodiligence is merely the means of achieving this endpoint, ie, determine risks and prevent ADRs.

From 1969-2002, about 2.3 million ADR cases were reported to the US FDA, of which about 80 percent originated from reporters in the US. It is likely that no country in the developing world would have received such a large number of ADR cases in the same time period. As America and the EU represent the bulk of the global pharmaceutical market, it is expected that most ADRs are reported from these regions.

Western society also has the mechanisms to conduct lawsuits on errant companies that compromise patient safety, and consumer alertness have also led to significant numbers of ADRs being reported. The governments of these countries also emphasize on public health and issue public safety alerts based on safety information that becomes available.

Government schemes like the Yellow Card scheme in the UK and MedWatch in the US ensure that consumers and Healthcare Professionals (HCPs) know where to report ADRs. In some countries it is even mandatory for the HCPs to report all ADRs that they are aware of. The media plays a significant role too, such that the first headlines of a significant safety alert may even appear in financial journals like The Wall Street Journal rather than in scientific health journals.

As the pharmaceutical market and its regulations continue to evolve in the developing countries along with increasing awareness among the consumers, the importance of pharmacovigilance is likely to grow. Perhaps this may give rise to a shift in approach from pharmacodiligence towards pharmacovigilance.

Protecting Public Health
The fundamental driving principle of pharmacovigilance is in safeguarding public health. The pharmaceuticals industry has an important role to play since it is at the center of the ADR information flow. In most cases, it is where the information is received (from patients or HCPs) and relayed to the regulatory authorities. The responsibility of industry goes beyond just collection and reporting. Also included in its list of activities are signal detection, risk-benefit evaluations and taking appropriate action to mitigate avoidable risks to the patients.

A robust pharmacovigilance system is essential for any pharmaceutical company. Regulatory authorities have instilled regulations and guidelines where non-compliance can lead to severe disciplinary action.

Many countries in the Asia Pacific region have well-defined pharmacovigilance regulations, eg, India, Vietnam, Malaysia, Australia, Japan and Singapore. Pharmaceutical companies with a headquarters in the region have expanded in the past few years and many have operations across the globe. Examples are India: Ranbaxy Labs, Dr. Reddy's Limited; China: Zhejiang Huahai Pharmaceutical, Zhejiang Hisun Pharmaceutical; Malaysia: Hovid. Companies are under increasing pressure to adhere to local regulations. They also have to keep abreast and comply with the global regulations that are applicable in the countries where the companies' products have authorizations.

In order to sustain growth, companies need to increase their portfolio by either increasing the number of products in a certain market or the number of markets for a certain product. Both these scenarios demand either a setup of pharmacovigilance departments or an expansion of the existing capabilities.

Both innovator and generics companies operate in Asia. An observation is that the pharmacovigilance regulatory expectations in the region do not distinguish between generic and innovator companies. Therefore, generics companies need to sustain the same level of compliance to these regulatory obligations as much as their innovator counterparts.

There are however, issues that companies need to be aware of before implementing a pharmacovigilance system:

• The Decision
As the setting up and maintenance of a system can have huge cost implications, the question is whether a pharmaceutical company invest in such an initiative. The answer is affirmative as non-compliance may put patients at risk. A non-compliant company may also face problems such as penalties by regulatory agencies, product recalls and consumer lawsuits - leading to a decline in company share prices and the erosion of shareholder wealth.

• Complex Systems and Processes
Setting up a pharmacovigilance system for a relatively new company could be challenging due to a lack of expertise and resources. It requires knowledge, investments and inputs from various stakeholders within the company like regulatory affairs, information technology (IT), sales, finance, marketing, legal, manufacturing, quality assurance, human resources and third-party vendors.

The systems need to work in harmony to deliver the following outputs in an efficient manner:

1) Customer call receipt and triage
2) ADR case processing & reporting (electronic or hard copy)
3) Periodic safety update reporting (PSUR)
4) Product quality complaints management (included by some companies)
5) Medical inquiries management (included by some companies)
6) Electronic safety database validation
7) Safety data exchange agreement management
8) Signal detection - risk-benefit evaluation
9) Risk management programs
10) Literature monitoring for ADR case reports
11) Training of company employees on ADR reporting
12) Global compliance monitoring
13) Audits and inspections management

• Lack of Harmonization in Global Regulations
Although global pharmacovigilance regulations have evolved from the same initial idea, there are some differences in different regions - posing another challenge for companies with global operations. An up-to-date knowledge of international regulations is essential. In many regions, the regulations are being revised and updated (eg, European Economic Area or EEA) and it is essential to keep pace with these changes. Examples of some variations can be found in Table 1 .

• Large Product Portfolio
How does one construct a foolproof system for the pharmacovigilance of several thousand global authorizations? Some generics companies have operations in more than 100 countries where there may be different authorizations (various strengths and formulations) in each of these countries for the same active ingredient. Handling such a large portfolio of products may turn out to be a management nightmare. In addition, mergers and acquisitions can also add to the complexity.

In order to penetrate new markets, overseas organizations are increasingly entering into business agreements with local companies in Asia. The pharmacovigilance obligations however, still remain and these companies need to define their responsibilities in the form of Safety Data Exchange Agreements (SDEA). These SDEAs form a legal binding tool that defines the role of each company.

• Knowledge & Manpower
Pharmacovigilance is a knowledgeintensive area of expertise. Since it is still a relatively new field in many Asia Pacific countries, there is a limited availability of people who are trained in this area. Table 2 illustrates the basic skills required for a pharmacovigilance employee.

• Different Countries, Linguistic barriers
There are also challenges in terms of differences in language (see Table 3).

• Evolving Regulations
As regulations evolve, they tend to become more specific and stringent. Companies need to enhance their knowledge, manpower and processes to cope with these updates. This could mean making drastic changes to already existing process workflows. Table 4 provides examples of changes in global regulations.

• Emotional Sensitivity
A consumer's perspective could add another dimension to pharmacovigilance - emotional sensitivity. This sensitivity could be further influenced, in a detrimental way, by media overreaction over reports of ADR which are known to occur with a particular drug. Physicians may also be skeptical about reporting ADRs to the company, thinking that this may affect their own image and reputation.

There may be sensitivities due to cultural variations. In a conservative society for example, inquiring about the pregnancy status of a young teenage girl as a part of a risk management program like iPledge for isotretinoin, could be deemed inappropriate by the patient. Therefore, certain local adaptations in procedures at a local level may be needed.

• Product Liability Implications
A general public perception in certain regions may be that if a company is reporting ADRs on a regular basis compared to another company that is not reporting as many ADRs, the quality of former's product is probably not as good as that of the latter. Certain regulatory authorities may also share this perception, leading to heightened anxiety for the company that is rigorously following pharmacovigilance best practices.

• Cost Implications
A good pharmacovigilance system is dependent upon Information Technology (IT) systems and human resources. There are various commercially available safety database systems which provide a backbone to the data management of ADR cases. These software applications serve as repository of ADR cases from across the globe and can be configured to schedule reports for global regulatory authorities and the analysis of the data for signal detection.

However, these systems are expensive to purchase and maintain and require validation efforts before they can be put to use. The majority of the cost component can be attributed to the following activities: cost of the software, licenses, hardware, validation of the database, implementation of the company's specific workflow, annual maintenance, training, recurrence cost of IT platform license, Medical Dictionary for Regulatory Activities (MedDRA) Dictionary subscription, World Health Organization Drug Dictionary (WHODD) subscription, third party application licenses, software upgrades/new versions, extra features/customizations.

Even with the use of varied software, pharmacovigilance continues to remain a laborintensive activity. Personnel are required for data entry, quality control, medical review, generation of periodic reports, signal detection activities and the maintenance of these systems.

Business Models - In-House vs Outsourcing
Given the complexities in managing these challenges, companies choose from various types of operating models, namely the "outsourcing model" or the "in-house model". Both these models have their respective strengths and weaknesses and the choice of model is dependent on certain key determinants.

Any company, either generic or innovator can follow any of the following business models for pharmacovigilance:

1. All activities in-house
2. Partial activities outsourced to a Contract Research Organization (CRO)
3. All activities outsourced to CRO

Activities that can be outsourced to a CRO include:
• Expedited reporting: Capture of ADRs in an electronic database, quality control, medical review and analysis of Individual Case Safety Reports (ICSR), Reporting (E2B, CIOMS)
• Periodic reporting: Generation of PSURs, narrative writing, etc.
• Monitoring of ADR literature
• Safety data exchange agreements
• Validation of electronic safety database
• Signal detection activities
• Product quality complaint management
• Medical inquiry management
• Risk management programs
• Training of company employees on ADR reporting
• Pharmacovigilance audits
• Department setup/restructuring

Each model has its own pros and cons. Keeping all activities "in-house" offers greater control on the flow of data; however it can be expensive and time consuming to setup and update. Table 5 provides some of the differences between the "in-house" and "outsourcing" models

Pharmacovigilance related expenditure is a "bitter pill" that every responsible pharmaceutical company has to swallow. However, this pill is necessary for ensuring patient and public safety. A robust system at the industry and state level can ensure that unnecessary and avoidable risks to the patient are minimized. The challenges for achieving this are many and the right approach can help to ensure that the desired results are achievable.