A Closer Look at Drug Safety

By Doniel Jackson, M.D., Managing Director, Pharmacovigilance and Medical Affairs, ICON Clinical Research

Today, pharmacologic therapies are often the first line of treatment for many diseases, including most chronic conditions. Drugs that control diabetes, relieve pain, ease respiration, control blood pressure and alleviate depression have become integral to the good health of millions.  “Lifestyle” pharmaceuticals such as drugs that treat sexual dysfunction and aid in weight loss, have become wildly popular among consumers.  People are taking more medications than ever before. According to the FDA, in the last 10 years the number of prescriptions filled in the U.S. has risen over 60%, to 3.1 billion.

With so many people taking so many different medications, the science of Drug Safety has assumed increased urgency for researchers, regulators, doctors and consumers alike - especially after the well-publicized recalls of once-popular drugs like Celebrex and Vioxx, and the plummeting fortunes of others (e.g, estrogen replacement compounds). Pharmaceutical product recalls are disastrous on many levels. First and most importantly, patients and their families suffer.  But what is more difficult to quantify is the simultaneous negative impact on the medical profession, regulatory agencies and the pharmaceutical industry –each incident, potentially eroding their credibility   Indeed, in some cases, the failure to adequately plan for and address questions of a product’s safety profile  has had devastating legal and financial consequences for pharmaceutical companies.

For all these reasons, today’s pharmaceutical, biotechnology and device manufacturers are dedicating more resources than ever to risk management, safety surveillance and pharmacovigilance.

Safety surveillance assumes more importance.
Drug Safety has become a high priority for regulatory agencies in recent years, particularly in the U.S. There have been three recent publications from the FDA’s Center for Drug Evaluation and Research, aimed at providing more definitive guidance to drug developers in an increasingly complicated scientific development mileau in which disease modifying agents, far more potent than their predecessors, which were typically designed to alleviate disease symptomatology.   The publication of these papers signals an increasing determination by regulators to make a real difference, especially after the safety problems seen in the 1990’s.Perhaps the most significant evidence of this shift in regulatory priorities is that we are now seeing more funding and regulatory ‘bite’ for the agencies responsible for public health.

Three key documents
The first document, a concept paper issued in March of 2003, titled “Pre-marketing Risk Assessment  the Center for Drug Evaluation and Research (CDER) emphasized the importance of generating risk information during clinical trials, and called on drug developers to design trials so that they produce sufficient and appropriate safety data. The paper contains recommendations on study size, database criteria, sample collection and packaging. This document is very instructive not only because it presents  everything the FDA expects in terms of documentation, but because it offers techniques for gathering and assembling the required data.

The second document  titled “Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment” (2005) provides specific directives on how to assess a particular type of product safety information, the so called ‘safety signal.’  Safety signals are early data which suggest a particular adverse event may require additional special attention when associated with the use of a pharmaceutical product. This document specifically addresses the role of pharmacovigilance in identifying and evaluating these signals.

The third document, “Development and Use of Risk Minimization Action Plans” (RiskMAP Guidance) focuses on the development of tools for effective risk minimization and risk management. In this 2005 paper, the FDA cleary establishes the standard that  risk management activities “should be continuous throughout a product’s life cycle” and that, in planning risk minimization activities, “sponsors should consider input from healthcare participants likely to be affected by these activities” including consumers, pharmacists, physicians, nurses and third-party payers.”
The scope and detail of these publications are a clear indication that the FDA is paying serious attention to Drug Safety issues, and the increased attention in this critical area could not be more timely in the evolution of Pharmaceutical product development

Though recent FDA efforts have been the primary focus here, similar safety initiatives have been implemented by the other leading Regulatory Authorities; though specific details may differ, their unifying themes are grounded firmly within the principles of modern-day drug safety as articulated through the tremendous efforts of the CIOMS working groups.   The pharmaceutical industry, with the release of these papers is better equipped to bolster the strengthening product safety obviated by the stunning advances in medical science on which future pipelines are predicated.  .

Harmonization in the Global Safety Arena
For most pharmaceutical companies, product development is geared not just to FDA or EMEA requirements; rather most clients develop drugs for the global market – CROs hoping to earn these companies’ business must have safety surveillance groups comprised of experienced personnel with an intimate knowledge of international regulatory requirements and harmonization issues.
Harmonization presents numerous unique challenges, particularly regarding safety surveillance.   Significant differences exist in what international regulators require in the development process or for marketing approved products to the public.   For example reporting of spontaneous adverse events is universally required.    However, US and Canadian regulators mandate reporting of consumer reported data in addition to the medically confirmed adverse event data required by other agencies  while consumers don’t always give very scientific descriptions of their medicinally-related experiences, a frequently reported event – however it’s described -- can provide a useful signal.
Among the worlds leading economic powers, there is such heterogeneity of economic structures that impact the production of medicines, rendering all but the most thoughtful harmonization efforts impractical.  In Drug Safety indeed ‘one size’ does not ‘fit all’ 
What is needed in the Pharmacovigilance sector is ‘intelligent harmonization’ -  collectively identifying and understanding the best practices of different countries and applying them in nations lacking these concepts.  Harmonization activities like this should only be employed when it has been agreed that implementation will result in improved public health.  . Methodologies are valuable, to be sure, but results are far more important. And in research as well as in medicine, the old rule still applies: ‘First, do no harm’.”

For more information about ICON’s safety surveillance and pharmacovigilance services, contact Dr. Doniel Jackson at 215-616-3260 or email to JacksonD@iconus.com