Pharmacovigilance, Then and Now
The pharmaceutical industry, encompassing the development, manufacture, marketing, and distribution of drugs globally is one of the most highly regulated industries in the world. Government regulations are designed to protect the health and well-being of the public consumer.
What is Pharmacovigilance?
According to the U.S. government, Pharmacovigilance is the process of monitoring pharmaceuticals for safety, reducing the risk and benefitting the patient in efforts to improve quality of life. The European Commission defines Pharmacovigilance as post-marketing surveillance to protect the public. Controlling authorities have the channels to order changes or modifications to drugs based on new signals discovered.[5]
Despite attempts to unify safety reporting across the globe through International Harmonization, differences in regulatory requirements still exist. The United States has some of the strictest guidelines for pharmaceutical regulatory safety.[10]
Pharmacovigilance and Drug Safety, The Difference
Drug safety and Pharmacovigilance both involve the same function of gathering and reporting adverse drug reactions. With drug safety however, data is gleaned from clinical trials and the post-marketing area and reported. This function is considered reactive. Conversely, Pharmacovigilance proactively examines the environment, scoping out signals and trends. The post-marketing environment is key as real-world conditions are carefully considered. Through data analytics new and greater signal detection systems can then be created.
The ultimate concern for companies is to identify hazards connected to their pharmaceutical product and to minimize risk to users. While clinical trials can tell a great deal about a product and how it will affect a controlled population, they don’t tell the whole story. Each of the “real world” variables involved in consumer use of medications or devices impacts product safety as well. Usually, a comprehensive audit must be completed to assess global regulatory compliance.
Pharmacovigilance started about 170 years ago, although it was not yet named as such at that time. It is structured activity in the professional health field, with important social and commercial implications aimed at monitoring the risk/benefit ratio of drugs, improving patient’s safety and the quality of life. In this commentary we report the milestones of pharmacovigilance up to the present day, in order to understand all the steps that have characterized the historical evolution; from the first reports, which were essentially letters or warnings sent by clinicians to publishers of important and famous scientific journals, up to today’s modern and ultra-structured electronic registries. The historical phases also help us to understand why pharmacovigilance helped us to achieve such important results for man’s health and for pharmacology itself, and to identify the challenges that await Pharmacovigilance in future years.
PV Activities
The processes associated with Pharmacovigilance involve several functions including:
· Collecting and managing safety data
· Reviewing case reports to detect signals
· Practicing proactive risk management
· Communicating with and informing company stakeholders and patients[5]
The Beginning of Pharmacovigilance
Keywords: Adverse drug reactions, History, Legislation, Pharmacovigilances, Signal detection, Thalidomide
The 1848 tragic death of a child in the United Kingdom by chloroform, moved the medical community to begin alerting others to the dangers of medicines, tonics, elixers and formulas. At first, physicians would post adverse drug reactions and specific case information to medical journals read by doctors, drugists, and laboratory scientists. This eventually led to the formation of various commissions created to investigate incidents, accidents, and fatal occurrances associated with medicines, their toxicity and purity.
In 1906 the U.S. Pure Food and Drug Act was passed calling for contamination free food and drugs, laboratory testing, and factory inspections. Its other purpose however, was to ban both foreign and interstate food containing harmful preservatives or adulterants and to stop mislabeled foods from streaming into the marketplace.[5]
More than 100 deaths due to the drug, Elixir of Sulfanilamide in 1937, lead to the Federal Food, Drug, and Cosmetic (FD&C) Act of 1938. It was not until 1962 in the U.S. that data for safety and efficacy of drugs (before pre-marketing submission) was required. The year 1966 ushered in a new era with a pilot study designed to conduct epidemiologic research using in-hospital monitoring to develop methods in epidemiology.[9]
Tragedy launched the entire system of Pharmacovigilance through spontaneous reporting of adverse drug reactions that was now organized, systematic, and timely.
What Has Changed in Pharmacovigilance?
In the 170 years since the first reports of adverse drug reactions, the field of Pharmacovigilance has grown exponentially. The huge global marketplace with its many complexities and challenges, product innovations, new advances in technology, and the everchanging landscape of regulatory requirements complicate drug safety while companies balance risk management responsibilities.
Pharmacovigilance functions to ensure the safety of pharmaceuticals, vaccines, plasma derived therapies, and medical devices. PV experts must constantly adapt to the rapid advancement of therapies and technologies and meet the extreme demands of an ever-evolving regulatory system.
Pharmacovigilance in practice involves the continuous collection of safety data, assessment, monitoring, and reporting on compounds and medical products that are in the clinical development stage or the post-marketing phase.
Pharmacovigilance encompasses myriad and complex functions necessary to meet regulatory standards. The rapidly changing global regulatory environment, emerging therapies, new technologies, medical devices, and pharmaceuticals make modern day pharmacovigilance a massive challenge.
Pharmacovigilant practices are guided by local, regional, and international healthcare systems and regulations.[7]
The Food and Drug Administration (FDA) oversees approximately 20,000 prescription drug products approved for market and regulates more than 6500 product categories for medical devices. With a total 5.9 billion, dollar budget
regulatory activities involving human drugs accounts for about 33 percent of the FDA’s budget.[3]
New Drugs—Long-term Investment
According to the Tufts Center for the Study of Drug Development it takes anywhere from 12 to 15 years for a new drug to be brought to market at an estimated cost to pharmaceutical manufacturers of over $2.6 billion.
The timeline includes years of clinical study and evaluation by the U.S. Food and Drug Administration. This is to ensure drugs are safe and effective for humans who take them. Once medications are approved in the U.S., further studies are required to assure products are safe and effective for populations not previously studied in clinical trials.
Novel drugs are pharmaceuticals that meet the medical needs for some advance in medical treatment. These are considered “novel” because their active ingredients have not been previously approved in the United States.
According to the last year’s annual report the FDA’s Center for Drug Evaluation and Research approved over 50 novel drugs for use by individuals suffering from a number of medical conditions.[2]
The Problem for Drug Makers
Pharmacovigilance as an industry has undergone tremendous change in the last decade amid a rapidly expanding pharmaceutical industry. More stringent regulatory requirements, diverse and complex global reporting and compliance systems, and new technologies designed to further streamline the process of data collection and signal detection have created the need for more highly trained professional resources within pharmaceutical organizations.
Many companies however, are hampered with the inability to attract and retain qualified in-house personnel for Pharmacovigilance directly affecting scalability.
The entire PV arena is risky for companies as they grapple with decisions over cost effective ways to handle Pharmacovigilance, while meeting the demand from global regulation and regulatory agencies, new technologies, and possible automation of some PV functions.[6]
Outsourcing—The Solution to the Need for PV Personnel
What Outsourced Talent Brings to the Table
· Central point of contact in one streamlined service provider for PV and regulatory requirements
· Saves both time and money
· Global reach as companies can work with clients internationally, anywhere, including those located in the U.S., Europe, Middle East, Asia, and Australia
· Clinical and post-marketing PV services for a multitude of nations globally
Solutions to managing the complex regulatory issues help free up time, energy, and resources, allowing companies to focus on consumer use and health, and reinvest earnings into developing and producing new drugs.
Why Choose From a Pool of Professionals Outside the Company?
Outsourcing reduces the cost for small to medium sized pharmaceutical companies experiencing:
· Rapid and unexpected increase in workload
· Personnel shortages
· Temporary lack of specialty trained staff resources
Qualified PV personnel perform a range of functions that include:
· Creating and Maintaining the PV system files
· Case processing
· Reporting
· Signal detection
· Updating and Maintaining a database of safety information
Reasons You Should Outsource Pharmacovigilance
· You don’t have time the time it takes to interview qualified candidates
· You have regulatory deadlines that won’t get met without immediate attention
· You may have to rework some processes or paperwork if you don’t get PV professionals immediately
· You lack the time needed to install/train new employees
· You need someone to step in seamlessly to pick up where another PV professional left off
According to Glassdoor, one of the nation’s leading employment recruiters, it takes the average organization about 24 days to hire a prospective candidate for a position. The time it takes to screen and interview an employee is valuable and always translates to lost revenue for the company.
Every day that goes by with an unfilled position is a day that an employee could have generated additional capital. Internal resentment from burned out personnel may also ensue, adding to an already stressed workplace leading to further loss of productivity.
Outsourced PV Benefits
Third party resources have solid expertise in PV functions and processes, as well as technology. They are unparalleled in their field and thoroughly know the systems they commonly maintain.
Reasons to work with outsourced talent:
· Top performers in their area of expertise
· Frees up management to focus on core capabilities
· Leading practices
· Former regulators
· Core competency in their specialty
· Mixed capabilities and experiences with other life science companies
· Investment in customer’s approach
· Knowledge from performing similar services for other companie
Goals moving forward:
· Greater efficiency
· Less reactive
· More proactive
· Focused on strategy
· Resource-intensive
· Transaction focused
What Drives Changes in the Roles and Focus of Pharmacovigilance?
· Regulator’s heightened focus on timely and accurate reporting of adverse events
· Drug corporation’s fear of paying hefty fines for insufficient or untimely reporting to regulatory agencies
· Increased focus by regulators on adverse events that originate outside of clinical trials and traditional help lines
These may include:
· Vendor interactions
· Outside patient assistance programs
· Social media accounts and specially sponsored websites
Why Outsourcing Makes Sense—The Move Towards Proactivity and Resource Efficiency
Because of regulatory changes, pharmaceutical operating models must now include greater focus on core capabilities including:
· Case Management for Adverse Events
· Aggregate Reporting
· Signal Intelligence
· Risk Management
Business Strategy for Future Growth
· Develop a benefit-risk profile for specific products
· Identify at-risk patients/users
· Global Networking
· Global coverage that must include knowledge of specific regulatory frameworks
· Enhanced Governance
· Strict and clear governance to include company-wide crisis management processes
Why Companies are Using Alternate Delivery Models
· Increased efficiency
· Increased capacity
· Use of internal redesign
· Full-scale outsourcing
Efficiently Managing the PV Delivery Model Through Outsourcing
Outsourced talent allows organizations the freedom they need to explore opportunities for growth, while continuously providing the framework for safety and compliance necessary to deliver the best product to patient consumers.
Internal Optimization—Trained in-house personnel work on activities of highest value.
Technology—Investing in new tools can streamline Pharmacovigilance activities and increase effectiveness for pharmaceutical organizations.
Consolidation—Creating a single unit of shared services increases staff efficiency, reduces redundancy, and makes for centralized control of Pharmacovigilance.
Outsourcing—The Answer for Scalability
By hiring a third party to handle some or all of PV operations businesses can pull in specific expertise that may not be easy to cultivate in-house.
These methods are cost effective and increase efficiency overall.
Issues of Company Concern
Internal resources, external expertise, and outside service providers may be cost efficient, but companies may not want to trade that for transparency, control, and high service levels. In response to this, certain core functions and services can be retained while risks to the business are reduced. Essentially, companies must find where gaps exist in their organization and make decisions for staffing based on those.
Care must be taken to ensure a third party can successfully handle quality execution of PV functions. By outsourcing pharmacovigilance, the responsibility for many drug safety functions is placed upon a third party. Depending on the organization, some or all responsibility for specific processes is transferred to that third party. Some functions will differ depending on the company.
Critical activities include:
· Collection of ADR data
· Case processing
· Creating Risk Management plan
· Preparing ideas for Risk Evaluation Mitigation Strategy
· Creating/submitting critical and timely PV reports
Benefits of a Good PVO Program
· Convert fixed costs to workload dependent costs
· Reduce staff needed to recruit, interview, hire, and train
· Instant access to experts, multi/hybrid talent
· Increased flexibility and capacity
· Increased efficiency and Return On Investment
Global outsourcing addresses: talent shortages, a rapidly changing regulatory landscape, and a company’s desire to invest in technology.
Safety in Outsourcing Pharmacovigilance
First time marketing authorization holders may lack the experience and resources to respond to all of the pressures involved in successfully bringing a product to market.
Once trust is lost in the pharmacovigilance sector, it’s very difficult to get back. That’s why it is critical to hire capable, professionally trained and vetted PV staff.
Moving forward, organizations will likely rely more heavily on outsourced talent for Pharmacovigilance. This will help in the response to high volume, complex regulatory requirements while adding scalability to the business.[4]
FDA’s Regulatory Authority, New Parameters
Drugs are used in the real-world marketplace where patients have comorbidities, take other prescribed medications and over-the-counter drugs and supplements. One important thing to realize is that a drug’s risk-benefit profile will change after market approval. Drugs must also be carefully monitored for safety after they have reached the real-world marketplace.[9]
Currently, limitations exist with post-marketing surveillance throughout the world. Many doctors and other medical professionals across the globe may not be adequately trained in the use of the ADR spontaneous reporting system. Some in the industry believe a shift in focus to more patient-centered Pharmacovigilance may be on the horizon.
The Future of Pharmacovigilance
Artificial intelligence and predictive analytics will most certainly play a part in future trends for Pharmacovigilance in medicine and pharmaceuticals. Computer generated models that can help regulatory agencies gauge risk-benefit once a product has moved to the real world will be called for as well.
While spontaneous reporting will still be needed in post market surveillance of products, newer methodologies and innovation with signal detection will be key.[1]
References
1Alomar, M., Tawfiq, A. M., Hassan, N., & Palaian, S. (2020, August 10). Post marketing surveillance of suspected adverse drug reactions through spontaneous reporting: Current status, challenges and the future. Therapeutic advances in drug safety. Retrieved October 26, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418468/.
2Center for Drug Evaluation and Research. (n.d.). New drug therapy approvals 2020. U.S. Food and Drug Administration. Retrieved October 26, 2021, from https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2020.
3Commissioner, O. of the. (n.d.). Fact sheet: FDA at a glance. U.S. Food and Drug Administration. Retrieved October 26, 2021, from https://www.fda.gov/about-fda/fda-basics/fact-sheet-fda-glance.
4Edwards, B. (2008, February). How should you safely outsource pharmacovigilance to an Indian contract research organization? Indian journal of pharmacology. Retrieved October 26, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038519/.
5Fornasier, G., Francescon, S., Leone, R., & Baldo, P. (2018, August). An historical overview over pharmacovigilance. International journal of clinical pharmacy. Retrieved October 26, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132952/.
6J;, P. (n.d.). Pharmacovigilance in crisis: Drug safety at a crossroads. Clinical therapeutics. Retrieved October 26, 2021, from https://pubmed.ncbi.nlm.nih.gov/29605513/.
7Kugener, V. F., Freedland, E. S., Maynard, K. I., Aimer, O., Webster, P. S., Salas, M., & Gossell-Williams, M. (2021, August). Enhancing pharmacovigilance from the US experience: Current practices and future opportunities. Drug safety. Retrieved October 26, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123099/.
8Laxminarayan, R., B, C. M., G, V. T., Arjun Kumar, K. V., Wahl, B., & Lewnard, J. A. (2021, August 13). SARS-COV-2 infection and mortality during the first epidemic wave in Madurai, South India: A prospective, active surveillance study. The Lancet. Infectious diseases. Retrieved October 26, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363227.
9Read "The future of drug safety: Promoting and protecting the health of the public" at nap.edu. National Academies Press: OpenBook. (n.d.). Retrieved October 26, 2021, from https://www.nap.edu/read/11750/chapter/7.
10Talbot, J. C., & Nilsson, B. S. (1998, May). Pharmacovigilance in the pharmaceutical industry. British journal of clinical pharmacology. Retrieved October 26, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873545/.