Introduction

The ever increasing number of commercial biotechnology ventures currently being formed has often been cited as being one of the many indicators of a rapidly changing world. Indeed, most of the technologies now being employed or contemplated are not only providing the promise of a new era of medical advancement but are also resulting in the creation of substantial new challenges and complexities for both regulatory agencies and companies alike.

At the same time, the move to establish world free trade and the accompanying creation of multinational economic trade groups, have resulted in the globalization of many industries, not least among these being that of pharmaceuticals. Free trade, however, has always centred upon the freedom of movement and the reciprocal acceptance of commercial goods. A major impediment to such free movement has always been the existence of national trade barriers, in the form of tariffs and restrictive or obscure regulation.

The current expansion of medicinal products into a global market, in conjunction with an intensification of the rate industry concentration, is occurring at the same time that general trade barriers and tariffs are being removed as market impediments. Regulations that hamper trade are being increasingly challenged and are either being removed or amended. Pharmaceuticals are, in a world-wide context, among the most heavily regulated products in commerce. By their nature, they have always been the immediate focus of any nation's controls for the administration of the health and safety of its citizens. The result has been the proliferation of independent standards by which drug products are accepted and controlled. With the globalization of drug production and the ever increasing cost of drug development on a world scale, the impetus is to attempt to harmonize the existing multiple standards of drug regulation.

Medicinal Product Registration & Control

The multiplicity of national drug regulations has, over time, led to sometimes tortuous registration processes, which vary widely from one jurisdiction to another. This has resulted in vast variations in application data for the same drug being registered with different regulatory agencies. Fortunately, the advent of the European Economic Union (EEC) provided an example of a forced environment of needed multi-state regulatory change. The EEC, comprising a market size of some 320 million, had considerable incentive to rationalize its trading activities, and in doing so launched upon a process of harmonization of its regulations to remove cross border restrictions on the movement of goods.

Medicinal products were ultimately included In this process. The scope of the task was immense, with widely fluctuating registration standards existing in the member states. Registrations of drug and device products were beset with often conflicting requirements and insufficient consensus on the acceptability of both standards and the data thereby created. Indeed, they and the general application of GLP, GCP, and GMPs vary in their regulation throughout the world. But it was recognized that the potential rewards were far reaching.

Progress has been surprisingly swift and the world-at-large looked on with increasing interest as segments of the EEC forged ahead and enacted controlling directives in ever increasing numbers. The International Organization for Standardization (ISO) quality system standards, known as ISO 9000 were adopted for the European general markets and subsequently forged mutual recognition for the manufacturing aspects of medical device manufacture. In parallel with these activities, the Paris based Organization for Economic Development and Co-operation (OECD) created multi-state consensus guidelines for the conduct of Good Laboratory Practice in safety studies among its member states. Thus, much credit for the impetus towards mutual recognition of standards can be attributed to the advancing development of the European Union (EU).

International Conference on Harmonization (ICH)

The evolution of the EU has led to the situation whereby three regulatory regions , the USA, Japan and the European Union (EU), now exist and have jurisdiction over a majority of the world's pharmaceutical market, and almost 95% of the research capacity. This can be seen to have had much to do with the creation of the International Conference on Harmonization (ICH) project.

The ICH is a unique regulatory project which has brought together the drug regulatory authorities of Europe, Japan and the US and experts from the pharmaceutical industry to discuss and deliberate on the scientific and technical aspects of product registration. The underlying purpose was to arrive at a consensus on recommendations to harmonize the requirements for drug registration of new entities. The intent being to reduce duplication of international drug development efforts and the avoidance of unnecessary delays in the availability of medicinal product introductions in participating states. All this, of course, was to be achieved while maintaining each independent regulatory agency's obligations to maintain public health and safety. This joint initiative between regulators and pharmaceutical industry was originally set up to provide a forum for discussion of the testing procedure requirements for new molecular entities, "to ensure and assess the safety, quality and efficacy of medicines".

There are six parties directly involved with the process. A number of selected observers and the International Federation of Pharmaceutical Manufacturers Association (IFPMA) are "guest" participants. The six official co-sponsors of ICH are the regulatory and industrial participants in the three ICH regions of Europe, Japan, and the United States of America. They are the European Commission (EU), the European Federation of Pharmaceutical Industries Association (EFPIA), the Ministry of Health and Welfare, Japan (MHW), the Japan Pharmaceutical Manufacturer's Association (JPMA), the US Food and Drug Administration (FDA), and the Pharmaceutical Research and Manufacturers of America PhRMA). Each sponsor party has two seats on the ICH Steering Committee. The addition of observers was made to provide links to non-ICH countries and regions, ie., the "rest of the world". These "observer members" include the World Health Organization (WHO), the European Free Trade Area (EFTA) represented by Switzerland, and Canada (Drugs Directorate, Health Canada).

The ICH Steering Committee, established in 1990, is central to the workings of the ICH. Its primary charge is to determine the policies and procedures for the ICH and to select regulatory topics for harmonization discussions. The harmonization topic discussions are then dealt with by Expert Working Groups (EWGs), each headed by a Topic Leader. Topics are selected by individual ICH members or by the EWGs, via the production of Concept Papers. Each topic is then subjected to a 5 step process for creation of consensus guidances, which is as follows:

Step 1: A six member EWG is created for the topic and a first draft prepared by a Rapporteur (one of the Topic leaders). Drafts can be for "guidelines, policy statements, recommendations, or points to consider". A draft consensus document is prepared and forwarded by the EWG to the ICH Steering Committee.

Step 2: A draft is signed by each of the six co-sponsors and forwarded to the three regulatory bodies (EU, Japan, USA) for regional consultation between government and industry. It is at this point that the observer status members may be included, ie. Canada, WHO, EFTA.

Step 3: The EU, MHW, or FDA designate a Regulatory rapporteur to collect comments and amends the "draft" from Step 2, or produces final draft for ICH EWG for signing and forwarding to the Steering Committee for adoption.

Step 4: A final draft is presented to the Steering Committee and signed by the three regulatory parties and recommended for adoption.

Step 5: The full recommendations are adopted by each regulatory body and formulated into their domestic policies and procedures.

Forty two guidelines and issues are presently under discussion or in development and individual biotechnology products issues have been identified. The topics cover Safety (including S6 Safety Studies for Biotechnological Products, presently at Step 1), Safety/Efficacy, (including Good Clinical Practice), Quality (Biotechnological Products including Genetic Stability, Step 5; Product Stability, Step 5; Cell Substrates, Step 1 ; and Specifications for Biotechnological Substances, Step 1). Additional items include development of a common Medical Terminology and Electronic Standards for Information Transfer.

Progress To-date

It is of interest to note that contrary to the regularly perceived notion of slow and ponderous bureaucracy, the ICH initiatives have resulted in the speedy adoption of significant documents and guidelines by the active parties involved. Five finalized guidelines have been adopted and recommended for implementation in Europe, Japan and the US. Included in these are guidances on clinical safety reporting and quality evaluation through stability and impurity studies. A further five draft texts have been released for regulatory consultation, including safety studies on biotechnological products. In October 1996, a guideline for genotoxicity testing was also released for consultation. As a result, some 24 guidelines have been finalized, with a further 9 under regulatory consultation. In addition, a move towards a common format and content for product registration was made in the initiation of a feasibility study.

What Next?

The Fourth ICH Conference is to take place July 16 - 18 1997, in Brussels, Belgium. This conference will, of course, review the results of the harmonization efforts to-date. More to the point however, the participants at this major political and pharmaceutical event will attempt to examine the effects of their efforts from a global perspective. Discussions are scheduled on the regulatory aspects of new and emerging technologies and how the participants can harmonize their approaches to them. No doubt the many advances on the biotechnology front are prompting their actions.

From a Canadian perspective, the industry needs to keep a close eye upon the effects of the ICH initiatives. Even though the Government of Canada has only observer status (via Health Canada) and thus no vote (its influence is limited), it is evident that adoption of any resulting ICH guidelines is to become part of its regulatory strategies. Indeed, the recent publication of the 4th Edition of the GMP Guidelines makes it quite clear that they are intended to be in line with both the existing and forthcoming ICH guidelines.

Some issues, presently arising, are clearly the result of the non-participation of peripheral groups which suddenly find themselves due to be bound by guidelines that are proving to be inappropriate for their products. A notable example is that of the generic industry, which is seeing some of the new entity requirements being applied directly to their products, clearly conflicting with the ICH mandate. Also the United States Pharmacopeia is coming under fire, because it has seen fit to adopt some of the ICH requirements for general monograph use where they were not so intended. Those companies wishing to export drug products to the United States, should take note of the fact that the FDA has stated that it will accept the use of any ICH guideline when it achieves Step 4 approval by the Steering Committee.

The Canadian Biotechnology industry would be wise to pay very strict attention to what is happening in the ICH forum and to voice concerns where necessary, otherwise it will find itself bound to requirements over which it had no control.

© 1997 CPCS, Inc.