Here is the second article on the history of the journey of a drug, please do not hesitate to check out the first part.
The lure of “beautiful” randomized studies
In addition to the elements previously reported about the deterioration of the quality of data from clinical studies, it is important to be able to understand the flaws of these “beautiful” studies touted by some followers of the‘Evidence-Based Medicine (EBM) which obscures expertise of the clinician and partnership of the patient in the treatment decision for him. During this crisis COVID-19, which has placed the planet in situation of a health emergency, some have lost all common sense and totally forgot what is the medicine : a subtle art.
For a start, it is important to remember that each person is unique and that talking to a patient, statistics can be meaningless. Indeed, for a given person, there is not 14%, 28%, or 87% chance of dying of such a cancer, this will be 0 (healing) or 100% (death). Medicine is an art when it is practiced by clinicians who know how to adapt to each person the best treatment for her, at a time t, in the taking into account of the globality of the person.
This does not call into question the concept of clinical studies well-conducted, ideally prospective, randomized, double-blind.
A study of quality begins with the drafting of a research protocol with specific objectives that should not change over time, as we have seen on a study conducted in patients with COVID-19, where suddenly a new “end-point” was added. This, of course, is opportunistic because the original criteria did not show efficacy of the product, and even more ill-advised methodologically, since the number of patients to be recruited to a study is calculated in terms of a statistical hypothesis on the evaluation criteria previously defined.
Because of the financial pressure, the follow-up studies is often carried out by people who do not have the necessary qualifications to do the research and/or do not have the means to work properly (for example, number of surrealist studies and records entrusted to a single ARC by the majority of the CRO).
The data is not analyzed before entry, which leads to make the analysis of big data from sources multifaceted, often lacking coherence clinic.
We then saw the emergence of the DSMB (Data Safety Monitoring Board) to “monitor” these clinical studies become “megatrials” with tens of thousands of patients, including a few dozen in each country where it wishes to market the future drug to satisfy the authorities. This makes it necessary to recruit researchers in each target country, preferably as ” prestigious “, the prestige is commonly linked to a title of Professor. It is as well that we have concentrated a little at the medicine research hospital at the expense of the medicine of city, obscuring the fact that patients, in general, do not have the same profiles as those of the city.
The heads of department have very quickly understood the interest of these studies very lucrative, some making the benefit their entire team in times of restriction of budget, others in their personal interest leading to serious conflicts of interest.
In France, the administration quickly wanted to have a share of the cake and set up financial agreements to recover fees which have again increased the cost of studies and have slowed down. Some hospitals have even wanted to manage it all by creating their own structure of clinical research with the hiring of ARC or of preparers in pharmacy for the management of clinical batches. Was the importance of the French market, the laboratories would open almost more of research centers in France, because of the administrative burden imposed.
But back to the DSMB ! This entity is “officially” an independent entity, made up of scientific capacity to look at the data from the study as it progresses to be able to give alerts in relation to ineffectiveness or adverse events. The independence of these structures became with the time more and more random… and under all of this…
Drugs & money, finance
The funding of the studies in question
The financer grants in general all the rights ! It is called the Promoter.
The research such that it is imposed costly studies on the drug are being conducted in the vast majority of cases by a promoter of the sector of the pharmaceutical industry that will have to be accountable to its shareholders of the relevance of its investments. The R&D teams are under pressure, they need to go quickly and produce positive results. The research is structured into team projects, whose management is interested in financial results, which leads in some cases to drift. The DSMB are funded by the sponsor and the investigators are also paid for by the sponsor, generally in proportion to the number of inclusions carried out.
All the floors the temptation can be great… Back in order…
Inclusion of patients : the patient must meet the “ inclusion criteria ” and does not subscribe to the “ criteria of non-inclusion “. It is therefore necessary to find the ideal patient for which the clinical observation will be paid several thousand euros. To be framed by the passed numerous clinical studies, I know how some investigators may have conducted “border line” to include at any price. During the crisis of the sars coronavirus, I myself for example asked why a patient of my acquaintance had not received oxygen during the first three days of hospitalization in pneumology then that she presented dyspnea (respiratory discomfort). Could it have been to reach a criterion of inclusion in a study in the difficulty of recruitment or by pure negligence ?
DSMB : competence and ethics are sometimes bad household with the interest of the sponsor.
But some of the DSMB are doing the work, and this is not always to the liking of the laboratory, as I’ve lived in a personal capacity as a Medical Director. Indeed, I have had to force the lab to discontinue the development of a product with two studies in over 12,000 patients each, and this at the price of extreme difficulties, and thinly veiled threats that made me understand how some people denouncing this type of problems had taken a bullet in the skull.
Analysis of the data by the sponsor : team project of the laboratory is the first to have the conclusions of the statisticians, themselves paid for by the sponsor when the analysis is outsourced. Participating in this type of meeting in a certain laboratory, in the pre-drafting of the report of the pivotal study (phase III) of a folder of WMA, what was my surprise to see substantial changes in data at fifteen days interval, and this in order to obtain a difference statistically significant between the two treatment groups. These meetings are “internal” are used to complete the file which will be presented to the coordinators of the study, often to the number of a country, which also represents the investigators from the countries in question, and that we will showcase at the launch of the product. It is necessary to add that this doctor, general, professor, received the title of honorary co-ordination consequential, encrypted, most often in several tens of thousands of euros, and that these fees are generally in the one-off payment imposed by the hospital administration.
The marketing of medicines are becoming more and more in a dynamic world, there is co-marketing and/or shares market to reduce the risks inherent in the research. There is therefore a de facto solidarity of the laboratories, often having multiple partners. It should also be noted that certain agencies of the drug are not completely neutral in their assessments when it comes to a national laboratory.
And yet, there could be things relevant to do ! For example, for hydroxychloroquine, a laboratory could have had the intelligence to develop a dosage form single-dose treatment with extended-release, which would have had the merit for the benefit of a new patent protector, allowing, in a strategy of sales volume, the maintenance of a cost of daily treatment acceptable on the entire planet and profitability for the laboratory carrying out the project. A deal win/win for the lab and for patients !
It is time to be lucid and stop pushing blindly a Evidence-Based Medicine diverted from its initial objectives.
What should be the role of the States to fund some basic research for citizens, without switches no longer in the state and the brakes of the administration. This is what should have been the French State during this pandemic in order to evaluate the association of hydroxychloroquine + azithromycin in early phase of the COVID-19. This is a serious mistake not to have done and to have spent colossal sums of money in studies inappropriate, particularly non-successful for the most part.
Some will discuss the deficiencies of budgets of research. A way to strengthen them would be, among other things, to check carefully the credits tax research allocated to the laboratories, expected to be spent on the French territory and some of which take advantage cheerfully to the country of origin of the concerned laboratories.
Finally, it would be important that citizens are aware of the planned obsolescence of drugs. In fact, in the last few years, the expiry date of the maximum of the medication is 3 years, while number of products are stable for much longer. It is a way to make sales and this enables you not to conduct the stability studies of the products on the years, as we did previously in pre-clinical research.
The result will be published tomorrow !
Author(s): Dr Violaine GUERIN for FranceSoir