New Horizons and Future Challenges

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The Sixth International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

The drug and medical-device industries are no different than others in that we now live in a global economy with worldwide markets. This is exemplified by the ease with which divisions of multinational pharmaceutical corporations can be relocated from one continent to another. As disease (and thus therapeutic-product development) tends to be international, knowledge of trends in areas such as standards of care, reimbursement and advertising/promotion of products is necessary to be able to effectively work with global, functional groups.

Driven by a desire to remove redundancy and delays, the International Conference on Harmonisation (ICH) (Geneva, Switzerland) was established in 1990 to focus on the harmonization of requirements for marketing registration and to improve the efficiency of developing new medicinal products. The six parties in ICH represent regulatory agencies and research-based industry in the three largest pharmaceutical markets: the United States, the European Union (EU) and Japan. Canada has official observer status with ICH and has been active in the process. The primary focus of ICH has been almost exclusively on the requirements for developing and registering products containing new drug substances in the EU, Japan and the U.S. An initial target for ICH activities was to develop a harmonized registration application for reporting data to the regulatory authorities. The Common Technical Document (CTD) format was completed in November 2000, and was implemented July 1, 2003.

The Common Technical Document — It’s Simply a Format

The CTD is an internationally agreed-upon format for the preparation of a well-structured presentation for applications to be submitted to regulatory authorities in the three ICH member regions. CTD format has five sections. Part one includes regional information such as application forms and overview items. Part two includes a summary overview of the data in support of marketing registration. Part three contains quality information on the chemistry, manufacturing and controls for the active ingredient and the dosage form (i.e., the active ingredient in the tablet, or cream, solution, etc.), while parts four and five contain non-clinical and clinical study reports, respectively.

ICH has been successful in achieving harmonization through the generation of the CTD, as well as some quality, efficacy and safety guidelines for new chemical entities (NCEs). However, many differences remain with respect to the implementation of this harmonized format.

There are differences in the enforcement of use of CTD format in the three member regions. As of July 1, 2003, CTD format has been mandatory in the EU and Japan. However, the use of the CTD in the U.S. is not mandatory; it has been “highly recommended.”

There are differences in the scope of use of the CTD format in the three member regions. In the EU, the CTD format will be applicable for all types of marketing authorization applications irrespective of the procedure (i.e., centralized, mutual recognition or national) and regardless of whether they are based on a full or an abridged application. The CTD format will be applicable for all types of products (i.e., new active substances, radiopharmaceuticals, vaccines, herbals, etc.). Currently, clinical trial applications are not harmonized within the EU; the European Directive for clinical trials comes into effect in May 2004. In the U.S., CTD format is highly recommended for marketing applications for pharmaceutical drug products and biologics, with the exception of blood and blood components. Herbals and dietary supplements are currently regulated as foods under the U.S. Federal Food, Drug, and Cosmetic Act (FD&C Act), and applicable regulatory documents are not likely to be filed in CTD format by manufacturers. Applications for clinical trials are not submitted in CTD format in the U.S. In Japan, CTD format must be used for new pharmaceutical and drug products, but not for generics or over-the-counter (OTC) products.

There are regional differences within the CTD format itself for the three member regions. Within the CTD, module one was designed to contain regional information. However, within the other modules, there are sections containing region-specific items. For example, case report forms, as well as possibly Integrated Summary of Safety (ISS) and Integrated Summary of Efficacy (ISE) information, are required in the U.S. as part of module five. For Japan, a tabulated list of clinical trial subjects is required as part of module five.

In general, the CTD is an application format and not an application type. In assembling dossiers for marketing registration, applicants are required to take into account regional guidelines relating to the quality, safety and efficacy of therapeutic products. The ICH guidelines on CTD format provide no information about the content of the scientific dossier, and they do not indicate which studies and data are required for successful approval. Each regulatory agency retains authority for its own specific regional scientific and regulatory requirements.

New Horizons and Future Challenges

Having accomplished its first step of implementing CTD format, ICH is now at a crossroad where it must revisit its original goals and identify ways to remove redundancy and delays in the research, development and review process for pharmaceuticals and biopharmaceuticals, as well as public concerns over rising costs of health care. The upcoming sixth ICH convention (Nov. 12-16 in Osaka, Japan) is aptly named New Horizons and Future Challenges. Challenging topics to be discussed at the ICH6 conference are listed on the ICH Web site (www.ich.org). These include shared experience on the implementation of the CTD, new pharmacovigilance topics, safety pharmacology, implementation issues related to existing ICH guidelines, partnerships in harmonization, gene therapy and future challenges facing ICH.

Global markets and recent international epidemics highlight the continued need for increased international harmonization, aimed at ensuring that good-quality, safe and effective medicines are developed and are available to patients. These activities must be pursued in the most efficient and cost-effective manner, preventing unnecessary duplication of clinical trials in humans and minimizing the use of animal testing, in the interest of the consumer and public health. Given these new horizons for the future, there are significant hurdles that will need to be overcome, including differences in language, culture, standards of care, and their impact on beliefs regarding the quantity and quality of data needed to demonstrate the safety and effectiveness of therapeutic products.

Differences in languages and cultures lie beneath the different drug-regulation systems and even definitions of “drugs” in the ICH member regions. In the U.S., products that are “for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man,” and have actions that “affect the structure or any function of the body,” are generally considered to be drugs pursuant to the definition in the FD&C Act. There are several categories of drugs, which have different requirements for marketing. New drugs and biologics are reviewed as part of the New Drug Application (NDA) and Biological Line Application (BLA) processes, respectively. OTC drugs are subject to a monograph system outlined in the CFR, or they can be approved for use following the review of an NDA for OTC use. An Abbreviated New Drug Application (ANDA) must be approved for generic drugs, and an NDA must be submitted for approval and marketing registration of new drugs.

In Japan, the term drug refers to 1) substances listed in the Japanese Pharmacopoeia; 2) substances (other than quasi-drugs), including dental materials, medical supplies and sanitary materials, which are intended for use in the diagnosis, treatment or prevention of disease in humans or animals, and which are not equipment or instruments; and 3) substances (other than quasi-drugs or cosmetics) that are intended to affect the structure or functions of the body of humans or animals, and which are not equipment or instruments. Drugs include both prescription and non-prescription products, and there are also other categories of medicines in Japan, such as drugs (including a limited number of products under the jurisdiction of local governments) sold by door-to-door salespersons who regularly deliver to homes. Quasi-drugs include products used to prevent vomiting, discomfort, bad breath, prickly heat, sores, to grow or remove hair, etc.

The EU currently has 15 members and will likely allow 11 or more additional countries to accede to the status of European Member State in the next few years. As defined in the codified Directive 2001/83/EC, a medicinal product is a substance or a combination of more than one substance presented for the treatment or prevention of a disease or to make a medical diagnosis or to correct or modify physiological functions in human beings. However, different approaches to the regulation of drugs by member states has led to significant variations in many areas including classifications of medicines in relation to access (e.g., prescription only, general sale, OTC) and the degree of generic penetration and the balance between generics, out-of-patent branded medicines and patented medicinal products.

With the EU as an example of an organization with different languages, cultures and backgrounds, where a harmonized clinical trial process is only now being developed within its own member states, it is evident that harmonization of requirements across diverse member regions is truly a slow process.

On top of this, there is a distinct set of hurdles for the rapidly growing biopharmaceutical segment of the industry. These include constantly changing technologies where legislation doesn’t necessarily apply (or exist), and the need to educate the public, politicians, and often regulators on the finer aspects of the quality, efficacy and safety of these innovative technologies and their potential utility as therapeutics. The importance and potential of biotechnology in contributing to the ongoing improvement of the health and welfare of individuals worldwide cannot be overstated, and the pharmaceutical and health-care industry is one of the key industries that will continue to have a positive impact on the daily lives of people around the world with respect to the treatment and cure of illness and disease.

Moving forward, ICH plays an essential role in a global economy in which the pace is set by new technologies and ingenuity. National economies, health-care and drug-reimbursement systems must be taken into account as they guide pharmaceutical development and industry markets. In moving forward, upcoming ICH meetings will be opportunities for regulators and industry of the three member regions to reach consensus on practical and realistic targets for greater harmonization of technical requirements. Although it may be slow, a collaborative process that respects cultures and value systems is the only way to achieve harmonization, and ICH is fundamental to improving the health and welfare of all individuals in the years to come.

The authors are regulatory-affairs consultants with the Pharmaceutical and Healthcare Group at Cantox Health Sciences International, a science-based consulting company with offices in Canada and the United States. Questions related to this article can be directed to Jennifer (JJ) Wilhelm at jwilhelm@ cantox.com.