In the past few years, national regulatory agencies have begun to cooperate more closely with one another in terms of pharmaceutical rules and regulations. In fact, substantial progress has been made in harmonizing drug approval requirements under the auspices of the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceutical Products (ICH). Despite these advances, the global pharmaceutical industry is still experiencing significant gaps in regulatory harmonization.
Issues with Pharmaceuticals
In any given market, drug discovery and development leading to regulatory approval is extremely risky and expensive. One in 10,000 candidates obtains approval at a cost of approximately $1.2 billion in the United States alone [1]. Due to lack of consistent regulatory requirements across national borders, the most pervasive drug development strategy is a staggered development process: first in the U.S. and/or Europe, and then to other markets. This has led to long "drug lags" in even the most developed countries, and much longer lags in other parts of the world.
Take, for example, the manufacturer of generic products that sought to gain approval for a medical product that was designed to be surgically implanted. The authorities requested a study of how this product affected animals, in particular the concentration of the residual implant of the product’s inactive chemical in rodent breast milk, even after the company had completed the BE study in humans. Because pregnant women do not intend to breast feed babies after the implantation of this product, this request made no scientific sense—and no such studies had been conducted by the original pharmaceutical company. The request by the authorities was based on a check list and had no real significance. While this specific government has increased its number of reviewers, some of these individuals lack the necessary experience for reviewing clinical studies. This inconsistency has created a drug lag in that country.
Thus far global harmonization efforts have failed to:
• Include significant and meaningful input from non-regulators
• Adequately represent the interests of emerging nations
• Successfully build global “regulatory capacity”
Furthermore, while various organizations engage in regulatory capacity-building with some success, results are extremely limited because often industry is neither a participant nor a target of harmonization efforts. Also, regulatory authorities and other regulatory stakeholders have failed to properly educate non-regulatory stakeholders. As a result, poorly understood regulatory practices are made subservient to other priorities by these non-regulatory stakeholders.
What Went Wrong in the Medical Device Industry
In the United States, medical devices—including products that range from bandages, syringes, and latex gloves to implantable defibrillators, CT scanners, and laser eye-sculpting machines—first became subject to regulation by the Food and Drug Administration (FDA) under the authority of the Food, Drug, and Cosmetic Act (FDC Act) of 1938. The scope and severity of the regulation became much greater under the authority of the Medical Device Amendments of the FDC Act, enacted in 1976, and later amendments, especially those of 1990.
By the early 1990s, firms in the industry found themselves subject to excruciatingly detailed, unpredictable, expensive and sometimes strangling regulatory strictures. Worse, consumers of the products—ultimately the patients themselves—suffered because of the regulation's destructive effect on technological development and withholding of already-developed products. Firms waited, often for years, to receive marketing approval from the FDA [2].
In Europe the situation was markedly different. Until recently, European countries imposed relatively little regulation on the producers of medical devices. Although the scope, detail and cost of the regulation varied widely, no European country practiced the rigid, elaborate, legislatively defined, centrally directed and enforced regulation imposed in the U.S. since 1976.
Instead, the Europeans relied more on the formulation of technical standards by professional organizations, leaving manufacturers free in most cases to comply or not comply with the established standards. Of course, purchasers could insist that products meet certain standards, and in some countries major purchasers, such as the National Health Service, were either required or urged to do so. In the 1970s, the Europeans began to develop a more restrictive system of regulation, but the adoption of the new system proceeded slowly. Only in the 1990s did the member states of the EU implement a more systematic and demanding regulatory system [3].
By the beginning of the 21st century, the European situation changed drastically, especially in countries that previously had little or no regulation. Notably, no evidence exists that European consumers in general had suffered because of the previous, relatively undemanding regulatory environment. In reality, many European patients actually benefited from the lack of regulations by gaining quicker access to new, more effective devices [4].
Notably, no evidence exists that European consumers in general have suffered because of the previous, relatively undemanding regulatory environment, and obviously many European patients have benefited by gaining quicker access to new, more effective devices [5]. In fact, the recent, nearly completed European changes have been driven not by safety concerns, but by the need to make regulations uniform throughout the EU in order to preclude their serving as trade barriers. As the desired uniformity is achieved, the common regulatory system will impose more regulation, even in countries such as France and Germany that already have relatively extensive regulation. The objection should be some measure of harmonized regulations that work toward a meaningful and scientific common standard.
Because regulatory requirements still differ among the major market areas, producers continue to confront troublesome and costly regulatory diversity. Hence, they continue to press for an even greater and, ultimately, global harmonization of the regulations [6]. The FDA Modernization Act of 1997 directs the FDA to meet with foreign governments to work out harmonization agreements. In addition, a Global Harmonization Task Force, including representatives of industry and regulators from the EU, U.S., Australia, Canada, Japan and other countries was created in 1992 to chart a course toward that ultimate objective. Since then its four study groups have been issuing documents for potential official adoption by the appropriate government authorities [7].
Prescription for Success: Strategic Capacity Building
The need for global regulatory harmonization has never been greater. The solution lies in the development of a better development strategy, also known as Simultaneous Global Development (SGD). Whether generic, innovative, small molecule or biotech, a necessary step in achieving SGD requires addressing the lack of globally consistent, science- and risk-based regulatory requirements.
The key to success lies in establishing strategic capacity building among both regulatory authorities and regulated industries. This capacity building effectively acts as the vehicle for leveraging regulatory harmonization efforts already underway, and empowers them through dialogue, training and external communications to non-regulatory stakeholders.
In terms of addressing trade considerations on a broader platform, the U.S., EU and other major groups are leading the way, and having an impact that is exemplified in lessons learned from the medical device industry.
Going forward, manufacturers across multiple fronts need to assist in the educational process related to regulatory issues, identifying divergent regulatory practices and soliciting feedback from industry leaders, going beyond just the regulatory to create practices that are sound from both a regulatory and public policy perspective. A strong link between regulators and industry can facilitate and expedite key issues.
While there is some consensus among many regulators that full harmonization may never be achieved across borders, the goal is to undertake initiatives and activities that would help move toward enhanced collaboration and agreement on requirements with regulators. Because regulatory requirements still differ globally, producers continue to confront troublesome and costly regulatory diversity.
Without greater support for international cooperation between and among regulatory authorities and their constituent stakeholders, patient access to important medical products will continue to be unnecessarily delayed -- particularly as development requirements continue to drive unsustainable cost models and significant delays in getting products approved across multiple countries. Ultimately, the shared goal is the efficient delivery of high quality, safe and efficacious therapies by advancing global harmonization of regulatory requirements for medical products and devices designed to improve quality of life for patients everywhere.
