March 3, 2013 | By Márcio Barra
No news updates this weekend, as exam’s and projects for the Master’s Degree start pilling up. So today, instead of a news update, i’ll instead post a small article on the International Conference on Harmonization history and constitution that I wrote for a class. Hope you enjoy it!
Before the ICH
The pharmaceutical industry has been, for long, one of the largest international industries. Going back to the 1980’s, global sales were estimated to be well over $300 billion dollars. Despite these numbers, it was a trying time for the pharmaceutical industry (1). In the wake of globalization (2), the industry suffered from a set of challenges at the time.
The World Trade Organization (WTO) didn’t have an agreement that addressed the then different testing requirements for pharmaceutical medicines, which in practice allowed for a country to ban a pharmaceutical product if it hadn’t been tested in his territory (1). These different sets of rules in the regulatory frameworks of the main global drug markets, alongside increasing pressure from governments and insurance companies to reduce costs, led the industry to go through a worldwide stagnation period, with slower drug development, higher prices for the consumer, and unfair competition between markets. The stakeholders opinion was unanimous – standards needed to be created (2) (3).
The creation of the ICH
The creation of the ICH – the International Conference of Harmonization, was fueled by trade reasons, to even out the competition between markets and end the aforementioned stagnation.
On one side, the USA had fixed a clear goal of opening up for the Japanese markets, with bilateral initiatives being carried by the two nations to foster trade between them.
Europe, on the other side, recognizing the value of a single drug market on the industry and the consumers, strengthened its resolve of achieving international harmonization of regulation within the EU at all levels, both in the pharmaceutical industry and governments. This came with the EC accepting the facts provided by the European pharmaceutical industry, regarding its constraints on the existing different drug registration procedures on each EU member state.
Within the EU, different stakeholders examined ways of standardizing the European regulatory requirements, and this experiment for inside harmonization was gradually deemed more and more viable by key stakeholders.
It also prompted the EU to, in 1988, to discuss bilateral harmonization with Japan and the EU, similar to those carried out by the USA (3) (4). This joint mission between Japan and the EU was comprised of representatives from the EU’s Committee for Proprietary Medicinal Products (CPMP) and the European Federation of Pharmaceutical Industries’ Associations (EFPIA). There, the idea for an international organization for harmonization for medicinal products was born (2), as the European Pharmaceutical industry, aware of the importance of the US market, was unsatisfied with only achieving bi-lateral harmonization with Japan (3) (4).
With that, the EC began discussing possible harmonization with both Japan and the US (1). Consequently, the International Federation of Pharmaceutical Manufacturers’ Associations (IFPMA) started organizing meetings between various stakeholders of the pharmaceutical industry and governmental entities of the Japan, US and EU (3) (4). With this, plans for a three way harmonization started to materialize, and in 1989, the three parties joined together in Paris, for the World Health Organization’s (WHO) Conference on Drug Regulatory Authorities. In 1990, the International Conference on Harmonization was created in Brussels, in a meeting hosted by the European Federation of Pharmaceutical Industries and Associations (EFPIA) (1). This involved industry stakeholders from the EU, Japan and the US as the main voting parties, and members from Health Canada, the WHO and the European Free Trade Area (EFTA) as non-voting observers (3) (4).
Since its inception, ICH wished to solve the harmonization problems between the three member regions. Its objectives are, thus, as follows:
- More efficient use of human, animal and material resources
- Reduce development times and unwanted delays of drugs
- End duplicate clinical trials
- Facilitate the simultaneous launch of a new drug in different countries, across all three ICH members
- Create guidelines to ensure that the highest level of safety, quality and efficacy is applied to drug development, with an eye towards globalization(5).
The main governing body of the ICH is the ICH Steering Commitee (SC), established when the ICH was created. It is comprised of six co-sponsors and three observers. The sponsors are the EU, EFPIA, MHLW (Japanese Minister of Health, Labour and Welfare), JPMA (Japan Pharmaceuticals Manufacturers Association), FDA and PhRMA (Pharmaceutical Research and Manufacturers of America), each with two seats in the SC. The observers are the WHO, Health Canada and the EFTA. The IFPMA acts as a non-voting member of the SC. The SC coordinates the functions of its main work organisms, namely the ICH Working Groups, the MedDRA Management Board, and the Global Cooperation Group. The main ICH services provided by each organism are detailed in the following paragraphs (6) (7).
The ICH guidelines were the main output of the ICH in its first decade of existence, and are still one of ICH’s main focuses. (8) They are created by the ICH working groups, and are split between 4 harmonization topics:
Efficacy (for clinical testing and safety purposes)
Quality (pharmaceutical development guidance)
Safety (pre-clinical toxicity)
Multidisciplinary (topics which impact more than one area)
Guideline E6, the “Guideline for Good Clinical Practice”, in particular, had an extremely positive effect in the quality of clinical trials in Japan once it became fully effective on April 1, 1997, as Japan started to generate globally usable clinical data. The immediate aftermath was a significant decline in the number of clinical trials conducted in Japan (from 722 in 1996 to 500 in 1997 and, more recently, 498 in 2008), because of the higher standards and rigor required when conducting clinical trials as well as a reduced need to conduct clinical trials in this country.
Under the multidisciplinary guideline M4, ICH introduced the Common Technical Document (CTD), first proposed in 1996 by the industry and launched in 2003. The CTD is a document comprised of four modules for quality, non-clinical and clinical information, plus one regional module specific to each region. It was a big step in harmonizing submission procedures, as it made the exchange of information among drug regulatory authorities easier.
Since 2003, both EMA and the FDA have had confidentiality agreements in place, where both entities can exchange confidential information as part of their regulatory and scientific process (9). The arrival of the CTD (and more recently, its electronic substitute, the eCTD (10)) helped these communications, as both agencies receive the submissions for a new drug in the same format.
Implementation of the CTD standard format also extended ICH’s harmonization to non-ICH countries, thus easing up their regulatory processes and promoting a faster access to new drugs in these countries. The eCTD, created by the ICH M2 expert working group (11), is an attempt to create an electronic interface for the industry to use when submitting information to regulatory authorities, instead of using paper. The eCTD main advantages are:
- Reduction in administrative workload
- Reduction of physical archiving space
- Facilitation of the review process.
Another tool created by the ICH to improve harmonization was the MedDRA, a free standardized dictionary of medical terminology, established in 1999, with hopes of facilitating sharing and use of medicinal products in humans. Its scope includes pharmaceuticals, vaccines and drug-devices products. This dictionary is maintained and developed by the MSSO (Maintenance and Support Services Organization), under the direction of the MedDRA Management Board, and it is updated two times a year, in March and in September
Although initially established for use within the US, Japan and Europe only, the MedDRA is currently used worldwide (13).
Global Cooperation Group
The last main harmonization activity conducted by the ICH is carried out by the Global Cooperation Group, established in 1999 alongside the MedDRA.
In the first decade of the ICH’s existence, it mainly focused on the development of guideline and standards for the ICH regions. Eventually, the ICH recognized a growing interest in the ICH services beyond the ICH countries, and thus created the GCP to better help information sharing between the ICH and the interested countries. Since its creation, it was expanded 2 times, the first in 2003, with the endorsement of a new mandate that invited five Regional Harmonization Initiatives (RHIs) to participate in GCG discussions, namely APEC, ASEAN, EAC, GCC, PANDRH and SAD. The second occurred in November 2007, as a direct response of the ICH to the more than ever worldwide reality of drug development. Regulators from Australia, Brazil, China, Chinese Taipei, India ,Rep. of Korea, Russia and Singapore were invited to join in the GCP (8).
In short, the ICH was created to deliver health care technology providers a common, almost global regulatory framework for them to develop their products. The ICH’s work is far from over, as more and more regulatory scrutiny is demanded from manufacturers and investigators and more pressure is applied to pharma companies to increase data transparency (14), who look up for ICH’s guidance.