Clinical research in the era of personalized medicine
One of the most impressive examples of a personalized anticancer drug is crizotinib, which is effective in treating only 4% of patients with lung cancer. The cells of their tumors are characterized by a specific chromosomal rearrangement, revealed in 2008 by the Hiroyuki Mano group from Jichi Medical University, Korea. This rearrangement leads to the appearance of the protein ALK-EML4, which is the result of the fusion of anaplastic lymphoma kinase (ALK) with EML4 (echinoderm microtubule associated protein like 4 – a protein involved in the formation of microtubules). The emerging protein complex contributes to the rapid progression of cancer, but its activity is potentially suppressed by crizotinib.
The clinical trial of this drug was very unusual, as it did not have a control group. It included a total of 82 patients whose tumors expressed the target marker ALK-EML4. At the time of inclusion in the study, some of the patients already had difficulty breathing and swallowing due to the growth of the tumor.
The use of krizotinib had a truly magical effect on patients. Their tumors shrank almost before their eyes, in some cases the maximum effect was manifested within 48 hours. Patients literally got on their feet and began to lead a normal lifestyle. There could be no doubt about the effectiveness of the drug – even considering the small number of patients, the positive results were unambiguously statistically significant.
Research on trialIn addition to immediately saving the lives of patients, krizotinib and other recently approved targeted drugs for clinical use have become a prerequisite for a revolution in oncology.
Currently, clinicians are revising the traditional model of conducting clinical trials, taking into account the realities of the coming era of personalized medicine.
Traditionally, clinical trials consist of four phases. The purpose of the first phase is to clarify the dose-response relationship, that is, the selection of dosages of the drug that are safely tolerated by patients. In the second phase, the effectiveness of the drug is tested on a larger number of patients. Many drugs that look very promising at the stage of laboratory research do not pass phase II. In case of successful completion of phase II, phase III begins, in which a large number of patients participate and the effectiveness of the new drug is compared with the effectiveness of the standard treatment protocol. The last stage is the post-marketing phase, which continues after the drug has been approved for commercial use and is devoted to studying the long-term effects of its action.
Usually, to demonstrate the statistical reliability of the effectiveness of the drug, a large number of patients are included in phase II and III studies. They are randomly divided into groups taking a placebo or a test drug; at the same time, neither the medical staff, nor the patients, nor the researchers processing the results obtained in the clinic do not know which of the participants received the tested drug and who received the dummy. (More complex variants are also possible, with a large number of groups of participants and combinations of drugs and placebo.) The "gold standard" of evidence-based medicine is precisely such double-blind randomized placebo-controlled clinical trials.
However, recently it has become obvious that drugs that have performed well in preclinical trials too often do not pass clinical trials. This has prompted many specialists to think about the need to restructure clinical trials in such a way that they provide a quick, unambiguous answer "yes" or "no" instead of spending hundreds of millions of dollars and years (in some cases up to 10 years) on the initial phases of testing new drugs. To date, one of the record holders in this nomination is crizotinib, which has received official approval from the US Food and Drug Administration for two years. This success is a clear indicator of the power of personalized medicine.
The frequency of failures during the last phases of drug development
Data for Phase II for 2008-2010 and phase III for 2007-2010.
(Arrowsmith, 2011, Nat. Rev. Drug Discov. 10, 87)
In addition, ethical issues concerning the conduct of clinical trials have surfaced, including the moral correctness of using a placebo or a standard therapy protocol. This issue is completely eliminated with a personalized approach to antitumor therapy, the postulate of which is the selection of patients to whom this drug will help with a high probability.
However, the identification of genetic markers predicting the response of patients to drugs for the treatment of non-oncological diseases turned out to be a much more difficult task. Therefore, it is not yet clear how the approach to planning clinical trials in other areas of medicine can be improved.
An exception to the rule?One of the few successes in the field of pharmacogenetics was the discovery by David Goldstein, director of the Center for the Study of Human Genome Variations, part of Duke University, of an allele predicting the response of a patient with hepatitis C to a standard therapy protocol.
Goldstein believes that it is possible to divide patients of different therapeutic directions into genetic subgroups that respond differently to treatment. However, unfortunately, there are few successful examples to date, and the results of genome-wide studies, which were considered a powerful tool for identifying genetic variants, do not allow dividing patients into populations suitable for conducting clinical trials. The reason for this is a huge number of rare mutations that can cause individual reactions of patients to treatment.
Hunting for biomarkersMost of the identified biomarkers do not allow to obtain an unambiguous prognosis of the patient's reaction to therapy.
Moreover, even if there is a reliable biomarker, clinicians usually cannot abandon the control group, since not all drugs have such an obvious positive effect as krizotinib. Therefore, in reality, the only way to evaluate the effectiveness of a drug is often to compare the results of its action with the results of using a standard treatment method or a placebo.
However, despite everything, at least the majority of oncologists-clinicians believe that the reform of clinical trials should continue and patients should be included in studies only after determining the characteristics of their genotype. Currently, the procedure is carried out in reverse order: researchers usually recruit a large number of patients, and at the end of the work they can conduct a retrospective genetic analysis of some of them.
Search for personalized medicinesIf the hypothesis is extrapolated to the stage of drug search, where researchers influence tumor cell lines with a variety of potential antitumor agents, then only a small part of all cell lines will respond to each specific drug.
According to experts, ideally, 2-6 thousand lines of human tumor cells are needed for pharmacological testing. However, to date, scientists have only one and a half to two thousand such lines at their disposal.
An important point is also the detailed decoding of the molecular mechanisms by which the drug slows down the growth of the tumor. This is necessary to identify new targets after the patient's malignant cells acquire resistance to the drug. For example, the same krizotinib increases the life expectancy of patients by 6-12 months, after which the disease inevitably recurs and the tumor ceases to respond to treatment.
Experts believe that throughout the entire process of planning clinical trials, scientists engaged in basic research should participate in it, along with clinicians. Moreover, it is the moral duty of doctors to obtain the most detailed information about patients even before their inclusion in phase I clinical trials. According to Ira Mellman, vice president of the oncology division of the biotech giant Genentech, it should be remembered that every patient makes a sacrifice by participating in a clinical trial, especially when testing experimental drugs that have no evidence of effectiveness.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the article by G.Vaidyanathan
“Redefining Clinical Trials: The Age of Personalized Medicine", published in the journal Cell.
23.05.2012