Outsourced Adverse Event reporting - A channel for medical research

Software solutions that lower risks in drug discovery, while lowering costs in developmental cycles are proving a godsend for pharmaceutical companies. Sanjiv Kapur, Senior Vice President and Head - Patni BPO & CIS goes a step beyond to propose that the outsourcing of Adverse Event reporting could open up a new channel for medical research

Every year, millions of dollars are spent on drug discovery, development and maintaining compliance, which allows millions across the world to enjoy a healthier life and provide the founding company its success.

The Context: Where?

Developing a new drug is a highly complex and expensive proposition and the stakes are high. Of approximately every 40,000 potentially interesting compounds, only one will become a medicinal product. The average duration of drug discovery and development process is about 10-15 years (of which one to five are done 'at risk' ie. without a patent on the compound), and requires major investment of human resources, capital and technological expertise. Every drug being researched goes through a number of pre-clinical and clinical trials, on animals and humans. Findings from these studies are carefully analysed by research scientists to establish efficacy and safety of the medicinal products.

The drug is marketed after approval is granted by the concerned country specific regulatory authority, for example in United States of America, US FDA (Food and Drug Administration) is the regulatory authority that gives approval. At this point the post-marketing, or maintenance, period for the compound begins. Post-marketing compliance remains the responsibility of the original patent holder as long as the compound is on the market, often even when the compound is marketed by another company.

The Issue: What?

The author is Senior Vice President and Head - Patni BPO & CIS

There is no possible programmeme of testing prior to the marketing of a drug that will find all its risks in real-world situations. In clinical trials patients are selected and are limited in number, the duration of trials is limited and the conditions of use will inevitably differ from some real world situations. Since most trials exclude the elderly, children, pregnant women, patients with multiple diseases, the studies' participants can not be 100 percent representative of the all real world situations where the drug is eventually used.

"Dying from a disease is sometimes unavoidable. But, dying from an adverse drug reaction is unacceptable".

Dr Vladimir Lepakhin
Geneva 2005

An adverse event (AE) is any unintended medical occurrence in a patient who was administered a medicinal product. The medicinal product does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. (ICH E2D) 1)

Adverse drug reactions are among the top 10 causes of mortality and the economic impact due to drug related mortality and morbidity is huge.

The success of regulatory authorities like US FDA in reducing drug-induced disease depends to a large extent on timely adverse event reports it receives from drug manufacturers and healthcare professionals. All pharmaceutical companies and drug manufacturers are required to monitor and report all serious as well as non- serious drug reactions to worldwide regulatory authorities like US FDA within a time period specified by the regulatory agencies. Strict compliance to these regulations is imperative. Delay in reporting these AEs by the company, may result in heavy penalties, tarnished company image, increased legal liabilities and even withdrawal of the drug from the market, resulting up to billions of dollars in lost revenue.

To provide context, 16 products recalls took place during the last decade.

• Withdrawal of one blockbuster product in the year 2004 resulted in $2.5 billion in lost revenue for a pharmaceutical giant.
• A top pharma company agreed to pay more than $1.2 billion to several affected subjects as a result of undisclosed adverse events related to the drug.
• Withdrawal and suspension of sales of a product of a pharma firm in the year 2005 due to severe AEs which generated nearly 2.4 percent of company's revenue resulted in crashing of companies shares.
• Following the withdrawal of a major, promising compound from development in 2001 a company's stock price crashed.

To meet the regulations, pharma companies established drug safety departments and strong pharmacovigilance practices with expertise in:

• Collecting adverse reports from worldwide,
• Marketed products,
• Clinical trials
• Literature reports and
• Other miscellaneous sources
• Assessing the adverse events for medical significance
• Reporting cases on both an expedited and periodic basis to the appropriate regulatory authorities worldwide

The World Health Organization (WHO) has defined pharmacovigilance as "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem" - with drug-related problems being further defined as "issues that affect the safety and safe use of medicines."

The principal aims of pharmacovigilance programmemes are:

• To improve patient care and safety in relation to the use of medicines and medicinal compounds;
• To improve public health and safety in relation to the use of medicines;
• To contribute to the assessment of benefit, harm, effectiveness and risk of medicines, thus encouraging their safe, rational and effective (including cost-effective) use;
• To promote understanding, education and clinical training in pharmacovigilance and its effective communication to health professionals and the public.

The Rationale: Why?

The global pharma industry is facing increased pressure from regulatory agencies to adhere to stringent timelines in reporting the AEs that may occur due to drug usage.

The increasing pressures from regulatory agencies and organisations, as well as the obvious financial and public image issues, demand that pharma companies do more than simply meet regulatory reporting deadlines. They must take a step back from the day-to-day reporting needs and analyse the data collected in order to look for trends in that data. The analysis of these trends will allow the identification of potential safety signals. To meet these analysis requirements, pharma companies need to expand the scope of their existing efforts.

Meeting pharmacovigilance regulations requires trained individuals to code and clinically assess cases. The safety team needs to keep abreast of regulatory requirements at regional, national and international levels. The workload will have peaks and troughs, particularly with marketed products that are taken seasonally. This variation in demand requires companies to plan staff to meet peak demand resulting in some resources being underutilised during slack periods.

Outsourcing such pharmacovigilance programmes and AE reporting systems allows pharma companies to free up valuable resource time, maximises output, and most importantly, reduces turnaround time with greater levels of accuracy. Outsourcing activities allows to the companies to focus their attention where and when it is needed most ie. a proactive, not reactive approach that ensures drug performance and overall safety. An important benefit is the reduced cost for database infrastructure and licence cost for costly software programmes. The greatest corporate benefit is the ability for a company to focus their internal, highly qualified resources on strategic business objectives rather than day-to-day data discovery and entry related to pharmacovigilance.

Of course, each company has its own strengths and weaknesses as well as its own philosophy for dealing with risks and benefits. Any outsourcing programme must integrate into the corporate philosophy and objectives of the client company. Some of the companies may want to outsource nearly all of their pharmacovigilance effort while others are only interested in outsourcing their call center and other companies may want to focus on outsourcing their medical review requirements. Matching the outsourcing offerings to the company's philosophy is critical for a satisfactory partnership between the client and the outsourcing firm.

The financial benefits of right sourcing pharmacovigilance can vary considerably depending on the degree of outsourcing of course. Most clients realise a reduction in the total cost of pharmacovigilance of between 20 and 40 percent.

The Method: How?

Case Triage: After receiving the potential AE Report from the call center, Safety Scientist confirms the minimum criteria to determine if the case is valid, performs necessary checks for duplication, initial or follow-up information by querying data fields, triage case for seriousness and expectedness, ensures that day zero is clearly mentioned in the source document and route the case for initial data entry.

Safety co-ordinator performs the initial data entry as specified in the data entry manual or as per client's SOPs and creates unique case ID for the initial case, For follow-up case enters new/updated information and routes the case for complete data entry, coding and preparation of safety narrative.

Safety Scientist performs MedDRA coding, writes safety narrative, determines follow-up plan and sets reminder in the system, subsequently the case is moved further in workflow for peer review.

Safety Scientist retrieves the case from the workflow and review against source document, for correctness of the data entered. Further the case is forwarded for medical review.

Medical reviewer retrieves the case from the workflow and checks for the medical accuracy of case and also writes pharmacovigilance comments when required.

Safety Coordinator follows-up with case reporter to obtain additional information as requested by Medical Reviewer, assembles expedited submission package, executes submission process, and supports client's completion of related submissions to the FDA, EMEA or other regulatory agency with strict adherence to timelines.