Postmarketing Study Commitment Trends for New Drugs: An Analysis of NMEs Approved in 2008
Given that the FDA Amendments Act of 2007 (FDAAA) took effect in late March 2008, the 2008 class of approved NMEs offered an early glimpse into how anxiously the FDA would wield its newly found powers regarding postmarketing requirements and risk evaluation and mitigation strategies (REMS).
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Nayan Nanavati, Vice President, Peri-Approval Clinical Excellence (PACE) Americas, PAREXEL International
Risk management for prescription pharmaceuticals is both a high priority and a significant challenge for the biopharmaceutical industry today. Numerous incidents involving the safety and risks of marketed pharmaceutical products in recent years have brought the issue to the forefront of public attention and regulatory scrutiny in the United States, Europe, and elsewhere around the world.
Some recent statistics highlight the issue of drug safety and risk. A study published in the Archives of Internal Medicine in 2007 showed that serious adverse events for prescription drugs reported to the US Food and Drug Administration (FDA) increased by nearly 260 percent between 1998 and 2005 – an increase that was four times greater than the growth in total out-patient prescriptions. In recent years, dozens of major pharmaceuticals have been withdrawn from the market or placed under stringent prescribing restrictions because of safety concerns. These product failures risked the health of patients, damaged the public trust of both the biopharmaceutical industry and government regulators, and represented investment losses of billions of dollars for the companies involved.
For everyone with a stake in the prescription drug arena – pharmaceutical companies, regulatory agencies, healthcare providers, and patients – the most important goal is to bring safe, efficacious medicines to market that appropriately balance benefits and risks for the targeted indication and patient population. Risk management helps achieve that goal by continually evaluating product safety to reduce risk.
For the pharmaceutical industry, the key to risk management is understanding as much as possible about a product’s risks before it reaches the market, and continually working to minimize those risks throughout the product lifecycle. That means investing in a robust risk management infrastructure, and promoting risk management as an essential part of the corporate culture. While the cost of implementing and maintaining an effective risk management program can be substantial, it pales in comparison to the cost of taking a product through development, only to have it fail to be approved or be withdrawn from the market because of safety issues.
What is Risk Management?
There is risk associated with every pharmaceutical product – a risk that is generally accepted if the benefits outweigh the potential harm. Managing that risk requires two essential – and challenging – processes. The first task is to assess a product’s risk and determine if that level of risk is acceptable, given the expected benefits. The second task is to find ways to reduce the risk while retaining the product’s efficacy. They are challenging because there are no accepted, objective criteria about how to balance the benefits and risks of pharmaceutical products.
The issues of risk and safety are further complicated by the nature of the clinical trial process. Even the largest Phase III clinical trials typically enroll no more than a few thousand patients. These trials provide significant data on the safety and efficacy of the compound for the target indication in its intended population. However, the limited size of clinical trials means that these studies cannot possibly answer every question about a product’s risks and side effects, such as:
- Are there rare events that will manifest themselves when more people take the drug?
- Does the drug pose different risks for certain patient populations?
- Will the risks change if a drug is taken over a long period of time?
Until recently, most risk management efforts have been focused on answering these questions by monitoring drug safety data from patients and prescribers after a product reaches the market. However, the concept of risk management has greatly expanded over the last few years to encompass every stage of product development. It is now generally agreed that the evaluation of safety and risk should begin at the earliest stages of drug discovery. The more that is understood about a product’s risks early in the development process, the better the decisions will be about how to appropriately manage risk for a specific indication and target population. It is also clear that a product’s risk profile evolves over time, which means that risk management must continue throughout a product’s lifecycle.
One step that many pharmaceutical companies are taking to enhance their understanding of product benefits versus risks is to expand their clinical trial programs during the peri-approval process – continuing to gather important safety and efficacy data during the time a product is undergoing regulatory review. This allows a company to gain additional data about a product and work with regulators during the review process to refine a product’s safety profile. Postmarketing pharmacovigilance programs also continue to play a vital role in monitoring the use of a product in a larger population to ensure that a product’s benefit/risk profile remains acceptable.
Regulatory Challenges
While the regulations governing risk management are crucial to ensuring the safety of marketed pharmaceutical products, they also present a challenge to the pharmaceutical industry as it tries to manage risk on a global scale. Although the FDA and the European Medicines Agency (EMEA) are actively promoting improved drug safety by providing a framework of laws and regulations designed to help companies better manage risk, they have taken different approaches and implemented “competing” regulations. While these regulations are beneficial in many ways, they also act as a barrier to better drug safety and risk management by making compliance more difficult, more costly, and less predictable.
The other major regulatory challenge for the pharmaceutical industry is the lack of any standards for evaluating the balance of benefit and risk. Current regulations do not provide a definition for an appropriate balance, and there is no currently accepted method for making this kind of assessment. So while there is a general consensus that risk management should include the concept of comparing benefits and risks, no validated scientific or regulatory framework exists to support it. Instead, risk is a subjective, case-by-case judgment by the sponsor, regulators, prescribers, and patients.
For pharmaceutical companies developing products for the global market, this lack of standards means that risk management in the near term must be addressed in close consultation with individual regulatory agencies for every product, with little standardization. Although the International Conference on Harmonisation (ICH) has some guidelines on pharmacovigilance, more work needs to be done between the industry and regulatory agencies to make the risk management process more transparent and predictable on a global scale.
Meeting the Challenges
Given these numerous challenges, what steps should pharmaceutical companies be taking to improve global risk management?
- Emphasize risk management and safety planning in every phase of the drug development process – beginning in drug discovery and continuing throughout the product lifecycle.
- Create a company-wide, proactive “safety culture” that establishes improved safety and risk management as corporate priorities; invest in the people, processes, and technology needed to improve risk management and protect the company’s most important assets: its products.
- Use the peri-approval period to gain additional information on product safety and risk in potential target populations, and to refine the product’s risk profile.
- Work closely with regulatory agencies to foster greater understanding about a product’s risk factors, and gain the agency’s insight into potential requirements for safety data or formal risk management plans.
- Continue to promote global regulatory harmonization to improve regulatory consistency, and work to develop a validated decision framework for objectively evaluating risk.
A company with a proactive approach to risk management will reap not only competitive benefits, but the benefits that come with enhancing its reputation among patients, regulators, lawmakers, physicians, insurers, and the many other important constituencies that ultimately determine the success of a company in the healthcare field.
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