Scientific/Medical Topic:

Birth of a new molecule Research into the development of new drugs Omar Pivetta M.D.
“…The need to adhere to strict ethical and regulatory frameworks is possibly the reason why only 1 of every 5000 new molecules developed, actually reaches the market”

During the last few decades hundreds of new molecules have been developed with therapeutic effects on several illnesses. This has happened in a number of countries and all such research has an element in common: namely the strict monitoring of scientific methods and the observance of no less strict ethical and regulatory frameworks. This need to adhere to strict ethical and regulatory frameworks is possibly the reason why only 1 of every 5000 new molecules developed, actually reaches the market. Those molecules or new drugs that do reach the market, do so after possibly as much as 12 years of research. This prolonged period of testing is necessary for assurance of the quality and safety of the final product.

Methodological aspects:
New drug research and development is based on the basic principles of a preclinical phase which consists of testing on animals in the laboratory and a clinical phase or clinical trials when the drugs are tested on humans. The first, also known as Phase 0, uses several experimental models as objects of study, mainly animals, with the objective of providing sufficient pharmacological¹ and toxicological² information to pass on to clinical phases (experimentation in humans) with a reasonable and predefined margin of safety.

Objectives of Phase 0 (preclinical):
* To define the profile of activity of the drug
* To define the profile of effectiveness and toxicity of the drug.
* To understand the absorption, distribution, biotransformation³ and excretion of the drug known as pharmaco-dynamics or the science of the action of drugs.

A chapter that deserves special attention in the pre-clinical phase is the evaluation of the toxicity of the new molecule (or how poisonous it might be). This is studied by different methods.

1) Acute toxicity, or how much of the drug is a lethal dose in a laboratory animal, is tested through several routes of administration in three different species of laboratory animals, at least one of which must be other than a mouse or rat (a non-rodent).

2) Sub-acute and chronic toxicity: In sub-acute the drug is administered for a period of one to three months. The minimum toxic dose, maximum dose tolerated and the phenomenon of tolerance and accumulation in the tissues of the animal are studied. The study of chronic toxicity involves studies that last three to six months or more.

3) Studies on reproductive processes of the species evaluate the potential toxicity in fertility, pregnancy and teratogenesis (the development of birth defects or mutations in children born to parents taking a particular drug, eg thalidomide). Evaluation of the potential teratogenic and mutagenic effect is most commonly tested by the administration of the drug for the lifetime of the laboratory animal model.

Clinical phase and objectives:
Experimentation with new drugs in humans is divided in four phases and each one has different objectives and different methodology.

Phase I: This is the first study carried out in human beings. In general it is carried out with informed consent (as are all 4 phases) in a group of 20 to 50 healthy volunteers with the main objective of evaluating dose, safety and tolerance ranges.

Phase II: This is carried out on volunteers who present with the disease for which the drug has been developed. The group may vary from 200 to 500 volunteers. The objectives pursued by this phase are evaluation of the selected dose, behaviour of the drug in sick people and the effectiveness of the drug to alleviate or cure the illness. This phase usually begins with international studies from many different centres around the world because of the large number of patients required to test the drug properly and the necessity of evaluating the drug in different races and cultures.

Phase III: This is the point at which researchers set out to establish the therapeutic effectiveness and safety of the new drug compared to currently available therapies for this disease. Phase III is carried out by recruiting up to 10,000 volunteer patients worldwide with strict selection criteria. Often the patients are randomly allocated to 2 or 3 treatment arms, eg one with the new drug, one with an existing drug and one using a “dummy drug” or placebo.

“…a very strict follow-up of the methods used to implement the study so that volunteers do not run unnecessary risks”

Phase IV: These studies are carried out after the drug is registered and marketed in order to evaluate its long term safety in large populations.

This whole research program of clinical trials includes a very strict follow-up of the methods used to implement the study so that volunteers do not run unnecessary risks, that they understand they can withdraw at any time and that their rights and privacy are protected. In addition very careful monitoring of the outcomes for patients ensures that reliable results are obtained from the study.

Regulatory Aspects:
Because the main objective of the team developing a new molecule is to market the final product, the research plan must first be presented to and authorised by regulatory agencies of the countries where the studies will be carried out. At the conclusion of the project the results must be validated for product approval and registration.

“The observance of this standard provides a public guarantee that the rights, safety and well being of the people studied are protected and the data is believable”

As was previously mentioned, the studies with large groups (Phase II and III) are carried out in a number of different countries many of which do not have local regulations for this activity. This resulted in the development of, and agreement to, strict guidelines so that the standard of implementation would be the same for all the countries taking part. In order to ensure this outcome, a group of experts representing different regulatory agencies and pharmaceutical research companies met in 1996. Using the principles of Good Clinical Practices (GCP) of the participating countries as a baseline, the International Conference of Harmonisation (ICH) was formed.

“…the obligatory participation of an Ethics Committee and the use of Informed Consent”

The countries that took part in the original meeting were USA, Japan and several representatives of the European Union (EU). The document that was developed serves as a guide for the conduct of clinical studies. It is considered to be of international ethical standards with clear guidelines for the design, direction, recording and reporting of research studies in humans. The observance of this standard provides a public guarantee that the rights, safety and well being of the people studied are protected and the data is believable.
These standards include, among other considerations, the obligatory participation of an Ethics Committee and the use of Informed Consent (a document by which the individual is informed about the features of the study, including possible harmful effects so they can voluntarily choose to participate or not).

Clinical research in Latin America
This region has particular features that have increased the level and quality of clinical research activity in recent years. Some of these features are:
• large populations contained in few cities,
• population without previous access to treatments
• good compliance to studies,
• low costs for sponsoring companies.

Some countries have appropriate regulations in agreement with the ICH, which facilitate the setting up and implementation of clinical studies. Argentina, Brazil, Mexico, Peru, Venezuela, Chile and Costa Rica are some of the countries that currently are participating in more studies.

Most of the studies carried out in this region do not have as their objective, the registration of the product in their country but rather to add their data to that presented to European and North American agencies. Once the product has authorisation for commercialisation in these countries, according to the region’s regulations, it can be registered and sold in the corresponding country.

Argentine Experience
In Argentina Regulation 5330/97 of the National Administration for Medicine, Food and Medical Technology (ANMAT, Administración Nacional de Medicamentos, Alimentos y Tecnología Médica) is the legislation that covers clinical research methods. It has been applied since 1997 and it deals with many of the requirements of the ICH.

“…it is the only Latin American agency that carries out inspections in research centres”

Having legislation of international standards has notably increased the number of clinical studies carried out in the country. During 1994, 64 studies were carried out and during 2002 almost 200 were undertaken. Almost 95% of the studies were Phase III clinical trials and they were mainly sponsored by multinational pharmaceutical companies.

A particular feature of ANMAT is that it is the only Latin American agency that carries out inspections in research centres. That is to say, it not only evaluates the feasibility of the project but also its implementation. The inspections began in 1997 and so far more than 200 have been carried out. The results demonstrate that the quality of the studies is comparable to that of other countries with ICH compliance.

Omar Pivetta M.D.
Instituto de Genética Médica
Argentina

Editorial comments:
Some definitions
1. Pharmacology is the science of the nature and properties of drugs, particularly their actions.
2. Toxicology is the science of the nature and effect of poisons, their detection and treatment of their effects.
3. Biotransformation is the change in form or structure of the drug once the patient ingests it.

This article is of particular interest to CF World Newsletter readers because the relative fast tracking of clinical drug trials in developing countries may result in the availability of new drugs for treating CF sooner than otherwise possible.

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