FORUM : The story of the journey of a drug is not a long quiet river. It tells the story in three acts. The first focuses on the creation of the drug : how ? In how much time ? That ? The second act will discuss how funding can intervene at the “right time”. Finally, the third and final act focuses on the conflict of interest, citing the scandal of the LancetGate.
The medical research was once laudable goals :
The purpose was the care of patients, in a context of benefit/risk and the development of new drugs for a specific illness with one or more treatment(s) of reference had for only aim to improve the efficiency and/or tolerance of treatment.
In 30 years, various parameters have transformed the drug industry in a business world organized, so lucrative that ethics has completely left the field of medicine that is now handled by people and interest groups that are devoid of humanity and that the health of patients is the least of worries.
All the world was not aware of this, there is an urgent need to open your eyes !
How to create a medicine ?
The development of a drug intended to be used in humans is in the field of research and development (R&D) and can be summarized in two broad steps : research, pre-clinical and clinical research.
In pre-clinical, several aspects are worked on :
1/ the discovery of an active principle to which you assign a name that will be its international nonproprietary name (INN),
2/ the dosage that is the formatting of the active principle as a function of route of administration (tablet, capsule, bulb, …),
3/ the implementation of in vitro test if applicable for the condition being studied,
4/ the testing on different animal species to evaluate before all the toxicity, and efficacy, there are animal models relevant to a specific illness,
5/ the evaluation of the stability of the product that allows to define its conservation conditions and expiration.
In the clinic, it goes into testing in humans, in 4 phases. This development has the objective of obtaining an authorisation for the placing on the market (AMM) in a clinical indication given. Example : treatment of rheumatoid arthritis
The Phase I analysis, tolerance of treatment. The “first administration in man” is performed on a small group of people, usually healthy volunteers, at different doses, inspired by the information gathered during the tests on animals, in particular, in monkeys (studies carried out in the past).
The Phase II goal is to find the dose most suitable for obtaining a therapeutic efficacy in a context of tolerance optimal with respect to the benefit/risk relative to the pathology studied. It is performed in people who are sick.
This phase of research is complex and takes a lot of time when it is done well. It is at this stage that one must also evaluate the potential drug-drug interactions when co-prescribing and the impact on comorbidities that a patient may suffer, in particular on the subject of hepatic and renal insufficiency, the liver, and the kidneys are the two preferential pathways of drug elimination.
Phase III can be summarized in general to a large study on a population of sick people where the drug will be tested against a placebo if there is no treatment of the pathology, either against a product that is already a point of reference, the interest being to demonstrate better efficacy and/or a better tolerance than the existing one.
For an objective assessment, the phase III studies should be conducted ” double-blind “, that is to say that neither the patient nor the doctor performing the evaluation of the treatment does not know the product administered. To do this, the inclusion in the study is done by a random draw of treatment (randomization) and clinical batches (drug or placebo) should be identical in their presentation.
The Phase IV case studies to deepen the knowledge of the drug. They have, over time, lost this purpose and have become studies of “prescription” to encourage doctors to test the drug once obtained the marketing authorisation.
Based on the difficulties encountered and can occur at all stages, whether pre-clinical or clinical. This requires very important investments.
A follow-up to the tolerance must be carried out after the placing on the market, this is what is called pharmacovigilance. This is a supervisory fundamental, since the use at a very large scale of a drug may reveal new side effects, events may be visible at a great distance from the administration and the complications secondary to the uses chronic usually can not be evaluated in phase III, the duration of which is limited.
Thirty years of drift in R&D
In the past, each country had a drug agency, who was responsible for the evaluation of the files and allocates the marketing authorisation. The clinical results were made country-by-country, in particular the phase III. This had relevance because these studies were carried out in the context of care in the country and with a population representative of the country.
It does not support the same way a patient with a myocardial infarction in France, in Belarus and Mali, for example, and the patient profiles are not the same.
Three major elements came to pervert the R&D in the pharmaceutical industry : profit, the globalization of clinical studies andhas centralised marketing authorisation for Europe.
In an economy of short-term, 10-15 years of R&D, it’s too long when you want a quick return on investment. At this stage, it should be recalled that in the original companies of “the pharma” were created most often by pharmacists or doctors, and that their development was often that of a family. Most of these laboratories, where quality of work and ethics were two key values, have all been sold with the time to become publicly traded companies with a central objective of profitability. There has been phases of concentration and deconcentration of this industry to the tunes of big bang/big crunch with outsourcing strategies the maximum of the expensive R&D that have led to the advent of the firms of “biotech ” in charge of finding new molecules and CRO (contract research organization) mandated to ensure the development.
To fund the screenings of molecules and begin their development, the biotech are looking for investors and can attract them with promises of profitability heavily underpinned by announcements promising results, are not always easy to decipher for non-scientists. But, it works, and biotech and pharmaceutical companies know how to perfectly manipulate the course of exchanges with the announcements made about the word “almost magical” PIPELINE “, translate the number of molecules “in the pipe” of the development. There is nothing better to create the movement in the stock market to announce the merger of structures, the creation of joint-venture or commercialization partnerships, then, that no certainty of a therapeutic that does not yet exist. Nothing better also to create movement in the stock exchange that the announcement of an arrest of development favouring an OPA (public purchase offer) potential to buy out a competitor.
A development of 10 years, it is a bit long to create movement, this is where the CRO.
In the 19th century the research was empirical and then, little by little, structured in such a way that each lab result had an R&D team and ensured it-even this part of the ” D ” of conscientiously. Doctors were solicited as” investigators ” to test the new molecules to patients. The advent of the collection of the informed consent of the patients has been very important to guarantee transparency to the studies done in the field, and Good Clinical Practices (GCP) brought a quality approach very useful in research. The business attaché of the clinical research (CRA) is born and the clinical data collected from the investigators were carefully recorded in notebooks to observing themselves carefully analyzed by the physicians of R&D to verify consistency before statistical analysis, this work often generating back-and-forth questions between investigators and physicians of R&D. The comments entered were of good quality, the information of tolerance were documented correctly, blind.
It was at this point in the good side of the concept of Evidence-Based Medicine Gordon Guyatt taking into account the expertise of the clinicians, the patient and clinical data is reliable, collected with transparency and ethics.
But, the quality has a cost and takes time, all settings are incompatible with a return on investment (ROI – return on investment) faster. The sub-contracting of clinical studies has been started, the CRO are born with the aim of making faster and cheaper. The notebooks of observation patients have not been analysed one-by-one by doctors and the collected information were entered in the databases whose consistency is becoming questionable.
The globalization of clinical studies
To recruit patients for a clinical study is also a long process, it was necessary to find solutions to shorten it. It has motivated investigators by paying them heavily and we started developing multi-country, especially in countries where patients were not supported by health systems that are efficient, as was the case in the 90s in central Europe. When 10 patients could be recruited per week in France in a study on myocardial infarction, it was easy to recruit 100 in Romania or in Hungary ; the investigators were motivated by the research opportunities offered to their patients who do not have access to health care and a valuable income.
But, to demonstrate a better efficacy and / or tolerance of existing products, particularly in markets as lucrative as inflammatory conditions, coronary heart disease, high blood pressure or diabetes, it is extremely difficult. Thus are born the studies of “non-inferiority” in which you just have to get an equivalence with the(s) product(s) referents, reaching to demonstrate a few microphones benefits to prescribing this new drug, and work, among other things, by the highly active structures of lobbying of the laboratories.
Two goals to this :
The centralization of the marketing authorisation
In Europe, a parameter fundamental also to be taken into account, has been the creation of the European medicines Agency, EMEA, initially based in London. The granting of a marketing authorisation has been therefore evolved over several years from a marketing authorisation by country with a mutual recognition procedure between the european countries to finish by a centralized procedure. At the introduction of the centralized procedure, a laboratory is defined very strategic in what country he was going to entrust the evaluation of its records, and the two main criteria were speed of response that would be given and the minimum amount of questions that would be asked, or even a minimum of carry out further investigations required. In this period, Sweden became the champion of the recordings, and France was virtually excluded from the process.
See you tomorrow for the continuation !
Author(s): Dr Violaine GUERIN for FranceSoir