Under the Microscope: The Impact of New Regulations on Clinical Development

Suzanne Gagnon, MD, Chief Medical Officer, ICON Clinical Research

About the Study

In the first quarter of 2009, ICON commissioned IMS Health to conduct in-depth interviews with 140 pharmaceutical and biotechnology executives, most of whom are leaders in pharmacovigilance or drug safety and have global responsibility. They represented a cross section of top-tier and mid-sized companies in the U.S. and in the top eight countries in the E.U. For further details and a copy of the full report, please contact Erica Hill at Erica.Hill@iconplc.com.

It's been five years since we reached a "tipping point" in attitudes toward drug safety with Merck's withdrawal of Vioxx®. We're now operating in a new era of drug safety marked by heightened scrutiny, public skepticism, and industry responsibility.

In recent years, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have imposed tighter standards for product surveillance and reporting to ensure the safety and effectiveness of medications over the long term and across wide populations. The goal is to reduce the societal burden of adverse drug reactions as reflected in patient welfare and healthcare budgets. For the pharmaceutical industry, of course, the burden extends to damaged reputations and enormous financial losses.

So how are pharmaceutical and biotechnology companies responding to these new safety imperatives? Are they able to cope at a time when they are also struggling to increase R&D productivity and trim development timelines? Understanding the complexity of the R&D process and the magnitude of the challenge, we commissioned a research study to explore:

What does the evolving safety environment mean for pharmaceutical operations in practical terms?
How is the industry preparing for closer scrutiny of its products, both pre- and post-approval?
Do companies have the resources they need to comply?

This issue of Insight is dedicated to reporting our findings and conclusions, which we hope will create further dialog on the topic and ultimately encourage drug sponsors to embrace new strategies toward drug safety. We believe that by adopting many of the supporting systems and approaches already available, companies can realize the goals of the new regulations with minimal strain on their organizational resources.

Regulators Scrutinize Real-World Use

The Pharmaceutical Research and Manufacturers of America (PhRMA) has noted that the industry suffers from a "trust deficit," despite the fact over the past 20 years, only three percent of prescription drugs have been withdrawn from the U.S. market for safety reasons¹. Since 2005, however, at least 10 high-profile prescription drugs have been pulled from the market, or had their impending launch scrubbed, due to safety concerns². This frequency suggests that something - be it scientific, regulatory, procedural, or clinical - was awry.

The difficulty - and the reason behind at least some of the withdrawals - stems from the fact that clinical trials conducted on subsets of the population simply cannot surface all potential side effects and adverse reactions to a medication. It is only when medications have been in use in the general population for extended periods that certain cautions become apparent. Therefore, regulators are increasingly focused on monitoring drug use and outcomes post launch.

The following more formal requirements are aimed at identifying problems in real-world clinical practice quickly so as to minimize risks:

Following the Food and Drug Administration Amendments Act of 2007 (FDAAA), the FDA has expanded authority to regulate drug safety. As a result, the agency has created two Internet databases to make clinical trial data more transparent: one lists clinical trial registries, the other clinical trial results. Through the "Sentinel Initiative," the agency is amassing information on the incidence of expected and frequent adverse events with marketed products.
At this writing, the FDA is collecting comments on draft guidance concerning its authority to require post-marketing studies and clinical trials in the event of new safety information.
Both the FDA and EMEA are increasingly following Japan's lead in requiring a formal post-marketing surveillance program as a condition of product approval. In the E.U., companies are now required to submit Risk Management Plans (RMP) with all new marketing applications. And, in the U.S., 25 drugs and biologics have approved Risk Evaluation and Mitigation Strategies (REMS), and that number is expected to grow significantly.
The European Risk Management Strategy (ERMS) launched an ambitious agenda in 2007 to protect the public's health, in part via more proactive monitoring of drugs in real-world use.
The EMEA has prepared Pan-European guidelines, emphasizing the importance of post-marketing reporting systems. Many E.U. member states are using long-term registries to comply with pharmacovigilance requirements and to support reimbursement decisions.

The Industry Takes Responsibility

Were these regulatory actions justified and how do companies view their added responsibility?

Just over half of those interviewed (52 percent) believed that the primary trigger for the recent regulatory changes was the rash of recent product withdrawals. Those in biopharmaceutical companies were even more inclined to hold this view (72 percent).

In the main, survey participants regarded tighter regulations as fitting; almost 60 percent considered it appropriate for the industry to shoulder more responsibility for drug safety at every stage of drug development.

The Impact is Far-Reaching

To comply with these regulations, companies have had to develop new clinical procedures and reporting mechanisms. Indeed, more than half (55 percent) of those surveyed reported that their companies now must constantly update their internal standard operating procedures for designing and conducting clinical trials.

It follows that three-quarters (77 percent) of interviewees believed that the industry as a whole has been acutely affected. Curiously, only 44 percent acknowledged a similar impact in their own companies - possibly reflecting a form of respondent bias in which individuals rate their own performance/knowledge above others.

Adapting to the new standards necessarily affects the work of everyone in the clinical area. The majority of participants predicted that the medical and regulatory departments would see a considerable increase in their workloads. (See Figure 1.)

Over 70 percent of interviewees from the medical and regulatory departments felt that they had a good grasp of the regulations and their impact. Far fewer (45 percent), however, believed that their associates in sales and marketing shared that understanding. This suggests that the clinical teams see a need for their commercial colleagues to be more fully briefed.

Patient Registries on the Rise

Drug sponsors are coming to realize that they need to invest in observational trials or "patient registries" to gather data on the use and effectiveness of marketed medicines. The larger organizations and biotechnology companies appear to be taking the lead in stepping up their Phase IV activities. (See Figure 2.)

Still, there is a surprising lack of recognition that patient registries offer value at all stages of the clinical trial process, with 40 percent of the respondents seeing them as a tool for amassing information post approval only.

Resources Will Come Up Short

With the new regulatory standards comes a need for increased investment in safety monitoring expertise across the organization - either internally or via external partners. Over half of the participants categorized the need for help as urgent (within the next six months) in their regulatory departments. And most (80 percent) called for added resources within the medical department in the next 12 months, while (70 percent) said the need would hit the commercial arm in the same timeframe. (See Figure 3.)

Although most respondents were fairly confident that they had the right expertise (as opposed to manpower) to deliver what was required, many acknowledged gaps. Twenty-one percent saw a need for supplementary experience in regulatory, 26 percent in medical, and 41 percent in the commercial arm of the business.

Implications for Pharma

It is clear that the regulatory trend is toward greater conservatism and that the industry's priority is to comply. Doing so entails understanding early in a drug's conception whether it will have the undesired effects in the wider population. And this is a mandate that requires global governance - regardless of where a company or its research programs are based. Although regulations for risk management and safety reporting are far from harmonized around the world, certainly a company's overall pre- and post-approval plans must be coordinated globally.

There are several shifts taking place that suggest that pharmaceutical and biotechnology companies may need to shore up their resources with additional manpower and expertise in critical areas:

Trial activities are increasingly being conducted in Eastern Europe, Latin America, and the Asia Pacific region. Thus, drug companies must have both the global reach and local knowledge to address critical geographical and societal variations in existing safety parameters.
Registries and observational studies are ever more important to supporting product safety goals across all stages of the clinical trial process, including the pre-approval phases of development. While patient registries cannot replace randomized clinical trials, they do provide more data on a drug's safety in the real world. Again, requirements vary by market, complicating planning and implementation.
Regulations for reporting adverse reactions in post-marketing use also differ by country, requiring local expertise.
The dual demands of meeting scientific standards while delivering a commercially-viable pipeline call for considerable creativity and flexibility in the use of resources. The need for additional help is already urgent in many regulatory departments and will be apparent in most regulatory departments and commercial areas shortly.

For all of these reasons, outsourcing safety processes is one viable option for easing resource constraints and/or supplementing internal expertise. This may be an especially sensible solution in biotech companies where in-house capabilities are stretched thin.

Drug sponsors must gather real-world data on a drug's everyday use, earlier in the development cycle, without delaying revenue generation. Companies that adopt new solutions to measuring drug safety (such as patient registries and anonymized patient-level databases) will realize important long-term advantages and potentially avoid expensive and even disastrous mistakes.

¹ www.phrma.org/issues/ and www.phrma.org/key_facts/

² These include: Raptiva®, Acomplia® (before making it to market), Trasylol®, Carisoma®, Prexige®, Zelmid/Zelmac®, Exanta®, and Bextra®.