Medicines from the "black lists"

New status for observational studies
Elena Volskaya, Oksana Alexandrova, I.M.Sechenov MMA
Remedium Magazine No. 3-2009

Reliable data on the efficacy and safety of medicines can be obtained only during the use of the drug in a wide clinical practice. Therefore, everyone who is concerned about the safety of pharmacotherapy is interested in post-marketing screening of routine drug use, in particular, through observational studies. However, the practice of conducting them causes serious criticism. In this regard, the pharmaceutical community has developed a number of measures to regulate non-interventional studies, including observational studies.

Openness as an incentive to research

The safety of medicines has been a priority topic for healthcare professionals for many years. Regulatory authorities in the field of drug circulation, pharmaceutical manufacturers, medical societies and professional associations, expert organizations create systems for monitoring the safety of drugs, collecting reports on side effects, their analysis and interpretation.

In recent years, experts and public figures have increasingly spoken about the need for transparency of data accumulated by pharmacovigilance systems. Repeatedly, from the stands of conferences and from the pages of specialized publications, there was a demand to provide access to information on the safety of drugs not only to doctors, but also to patients.

And here is the first precedent created: the legislator of norms in the field of regulation of the pharmaceutical sphere – the North American FDA administration in September last year published the first list of drugs with which a potential risk to the health of patients is associated – "Potential signals of serious risks – new safety information identified by the adverse events reporting system" ("Potential Signals of Serious Risks/New Safety Information Identified from the Inverse Event Reporting System (AERS)").

The first list (for January-March 2008) included 20 well-known drugs widely used in clinical practice. The list names the drug (MMN and trade name), observed against the background of its reception, a potential signal of a serious risk, additional information available to the FDA. The first publication was followed by the following – quarterly. Three lists of potentially dangerous drugs have already been published today, which include 43 drugs, including those that are widely used and absolutely necessary today. They are included in the list, despite the fact that their safety is not refuted by evidence. This is the intrigue of the new initiative. However, additional information is constantly updated in the lists. According to the FDA, the list includes drugs for which reports of adverse events have been received from clinics, doctors and patients, i.e. we are not talking about proven harmful properties of drugs, but about problematic cases from clinical practice.

The publication of this list, already called a "blacklist" by critics, is aimed at ensuring transparency of safety data and informing doctors and patients as quickly as possible about the possible risks of using drugs. According to the FDA, both doctors and patients will be more attentive when using these drugs, they will monitor the risks of the drugs mentioned in the lists, and this will help not only to increase the safety of their use, but also to collect additional safety information.

At the same time, representatives of the FDA explain that we are not talking about the proven harm of the listed drugs: the purpose is to signal a potential danger, they urge patients not to refuse treatment prescribed by a doctor, but to be more attentive to possible reactions and immediately report them to the doctor. It should be noted that consumer advocacy societies in the United States welcomed the publication of the lists.

However, in European countries, which no less called for transparency of data on the safety of drugs, the FDA initiative, to put it mildly, was adopted with caution. The traditional European approach is to comply with the principle of "presumption of safety" of the drug after its registration. Therefore, the very concept of signaling an unproven risk is critically perceived by both regulatory authorities (in particular, the Federal Institute of Medicines and Medical Products of Germany – BfArM was one of the first to speak out) and the pharmaceutical industry. Critics point to the incorrectness of operating with unconfirmed and unspoken risks of drugs, to the fact that publication in the "black list" will damage the image of drugs, and it will be very difficult to rehabilitate it even in the case of proof of safety.

However, the general trend is that in the EU countries it will inevitably be necessary to open information about the side effects of drugs. A group of experts has already started working in Brussels, whose task is to develop a draft law on the formation and publication of the European list of unsafe drugs. The pharmaceutical industry is lobbying for somewhat different approaches here than the FDA has demonstrated, namely, the development of clear criteria for inclusion in such a list and exclusion of drugs from it in order to ensure its greater stability, relevance and evidence.

The conflict with the publication of signal information about the potential danger of drugs and the prospect of classifying drugs as unsafe put manufacturers in front of the need to systematically obtain convincing evidence of the safety of their pharmaceutical products and clarify the true risks. Since clinical studies, no matter how large they are, are not enough for a complete picture, non-interventional drug studies, primarily observational (or observational) studies, enter the orbit of priorities.

But it is observational studies that have recently been increasingly criticized by regulatory authorities and the medical community. This type of drug research is threatened by the dubious fame of "frivolous", "commercial" events.

Observational research: Marketing or science?

Ask specialists working in the field of drug circulation what observational clinical trials are, and most of them will probably answer that this is a common way to promote drugs. It is the marketing aspect of observational research that is remembered first of all. In fact, the design of such studies is quite simple, they do not require the development of complex protocols. They are quite simple in execution, low-cost, do not require permits from regulatory authorities and additional insurance in case of damage to the patient's health, because they are carried out within the framework of permitted therapy, you do not need to look for experienced research doctors to conduct them, it is enough to agree with practitioners that they enter data on the studied drug into the questionnaire. When conducting observational studies, several goals are simultaneously achieved: the popularity of the drug among doctors, the accumulation of their experience in using it, the loyalty of doctors to the research sponsor company through partnerships, contractual relationships, obtaining data on the safety of drugs necessary for the manufacturer and regulatory authorities, using the positive results of such studies in publications for further promotion of the drug.

All these factors have led to the widespread practice of conducting observational research both in our country and abroad. Recently, these studies have increasingly attracted the attention of regulatory authorities. There are two reasons for this: firstly, the peculiarities of observational studies, consisting in involvement in the actual consumption of medicines, involuntarily suggests their use for marketing purposes. The temptation here lies in wait for both the sponsor and the doctor. After all, practitioners who prescribe medications to the patient, in case of participation in observational studies, receive a small fee for filling out the questionnaire submitted by the sponsor. The more questionnaires, the more the fee amount will be. This alone can be a motivation for increasing the prescriptions of the drug under study. Such a situation is capable of provoking unscrupulous manufacturers to imitate an observational study, and in fact stimulate the appointment of their own drugs to patients by material encouragement of a doctor, incomparably higher than a modest fee for a completed questionnaire. Suspicions of such unscrupulous behavior are also supported by the fact that observational studies are often initiated, organized and used by the departments of promotion and marketing of pharmaceutical products.

On the other hand, it became extremely clear that without representative data on side effects and other risks associated with the use of drugs, it is impossible to ensure the safety of medical care. Data on drug risks obtained when using drugs in large quantities would have to be collected for years if not for observational clinical studies. This is the important medical and social significance of such studies.

Non-interventional studies: definition and types

Observational studies belong to the category of so-called non-interventional studies, i.e. "studies without interventions". These are studies in which "the medicinal product (s) is prescribed in the usual way in accordance with the conditions set out in the permit for market sale. The question of "attributing" a patient to a specific treatment strategy is not decided in advance in the study protocol. This issue is being resolved in accordance with existing practice, and the prescription of the drug is clearly separated from the decision to include the patient in the study. No other diagnostic or monitoring procedures are used for patients, and epidemiological methods are used to analyze the collected data (as defined in Directive 2001/20/EC of the European Parliament and of the Council of April 4, 2001 on the approximation of legislation, rules and administrative regulations of the EU Member States concerning the implementation of high-quality clinical practice in conducting clinical trials of drugs for use in humans).

That is, non–interference in the doctor's decision on pharmacotherapy (as opposed to clinical trials) in the conditions of routine clinical practice is the main condition for conducting non-interventional studies. Such studies, as a rule, relate to clinical and epidemiological studies that determine the influence of treatment tactics on the results, including the frequency of complications and treatment outcomes. Accordingly, the object of non-interventional studies are those approved for medical use. Drugs prescribed in accordance with the indications and restrictions approved in the instructions (SmPC) at the discretion of the attending physician, who is not a research physician in the understanding of GCP. This is the main difference between non-interventional studies and phase IV clinical trials, where a strict protocol with inclusion and exclusion criteria and strict instructions to doctors on patient management is required.

However, non-interventional studies are conducted according to a plan that determines, in particular, the minimum number of cases, assessment methods, goals and objectives. But the conditions regarding the choice of the doctor are not set, he must carry out treatment at his own discretion, after the fact fixing the indicators concerning the studied drug.

Most types of non-interventional studies are known to specialists in the basics of evidence-based medicine and clinical epidemiology. These are cohort studies, case-control, "before and after", observational and some other types. However, so far none of the classics of the concept of evidence-based medicine [Gayatt G., Rennie D., 2003; Greenhalgh T., 2004; Fletcher R., Fletcher S., Wagner E., 1998; Vlasov V.V., 2001] has considered them from the point of view of regulatory requirements.

But now it's time for these studies to enter the regulatory framework. The prerequisites for this are as follows. Firstly, regulatory authorities felt an urgent need to create and systematically replenish databases on drug safety. In this regard, it is important for them to use the potential of manufacturing companies, often sponsors of research, to supplement the information at their disposal. Secondly, over the past 10 years, regulations concerning the confidentiality of personal data have been adopted in various countries and at the EU level (in Russia, the Federal Law "On Personal Data", 2006). The results of clinical and epidemiological non-interventional studies somehow affect such personal data, the use of which requires informed consent. consent of the study participants. And where informed consent is involved, a vote of ethics committees is required. Therefore, an essential element of the regulatory system must be involved.

And finally, observational studies required close attention of regulatory authorities, for these studies compliance with regulatory requirements is considered as a rehabilitating factor after numerous reproaches in their marketing orientation. In addition, not least observational studies have given grounds to discuss the problem of avoiding publication of data (“publicationbias”), when research results are presented in reports and publications in a stripped-down, incomplete form, beneficial to the sponsor of the study light.

As a result, the pharmaceutical community formulated requirements for compliance with high quality standards and transparency in relation to these studies, which fully complies with the newly introduced provision of the Helsinki Declaration as amended in October 2008: "Every clinical trial must be registered in a publicly accessible database before the first subject is included in it" (paragraph 19).

New regulatory requirements

In a strict sense, observations of the use of drugs in routine practice are not classical clinical studies. And yet, the development of regulatory requirements has actually leveled their regulatory status with clinical trials. Moreover, some requirements, primarily for observational studies, do not apply to classical trails.

Today we have the opportunity to summarize the requirements developed by various institutions and organizations of different EU countries – from ministries and departments to pharmaceutical industry unions. The most developed should be considered the "Recommendations for Planning, Conducting and Evaluating Observational Studies" of the Federal Institute of Drugs and Medical Products of Germany (BfArM), containing the main regulatory guidelines, and the Code of the Association of Self-Regulation and Self-Control of the Pharmaceutical Industry of Germany, where the requirements for the content of non-intervention research plans and quality management are formulated. Similar requirements are partially contained in the international codes of the pharmaceutical industry.

The main regulatory provisions are as follows:

• The head of the company's medical department, the same one responsible for clinical research, should be responsible for planning, management, evaluation of results and quality management in non-interventional studies. He is also responsible for funding such research.

• The head of the medical department of the company should also be responsible for the organization (in particular, the selection of clinical bases, negotiations with doctors and other medical specialists) and conducting non-interventional studies. This also applies to cases when employees of other departments participate in the organization and conduct of these studies. Quality management systems should be applied that ensure the validity and representativeness of the data obtained.

• The condition for the inclusion of a patient in a non-interventional study is to obtain his voluntary informed consent in writing (with the help of the clinical base, doctors and other specialists).

• Before conducting a study, it is necessary to obtain the advice of an independent ethics committee and its positive conclusion.

• Before starting a study, information about it should be presented in one of the available registers of clinical trials, including those supported by international pharmaceutical industry associations (IFPMA, EFPIA, JPMA, etc.). It is proposed to provide the following data: the name of the study, its purpose and objectives, the name of the supervisor, the trade name of the drug, INN, indications, according to which drugs are being investigated, the planned number of clinical bases, the planned number of patients (observed cases), contacts, links to publications (as they appear), the date of the last update of information.

• A summary report on the results of the study should be published a maximum of 12 months after the end of the study (last patient/last visit).

• Companies should describe in detail the main provisions and corporate rules for planning, conducting and evaluating research, as well as the corresponding verification of the data obtained in corporate Standard Operating Procedures (SOP, Standard Operating Procedures). These procedures should not contradict legislative acts and current codes of the pharmaceutical industry.

• Companies should regularly train their employees and third parties involved in planning, conducting and evaluating research results.

• Compensation to doctors for filling out questionnaires in observational studies should be moderate and not create an incentive for unjustified prescribing of the investigated drug.

In addition, for example, in Germany, a notification regime has been introduced in regulatory authorities for observational studies (in addition to the requirement to register in one of the registers): Sponsor companies or other initiators should report all planned observational studies to the Federal Institute for Medicines and Medical Products (BfArM) or the Paul Ehrlich Institute, as well as to the Association of Doctors Working in the CHI System and to regional associations of health insurance funds (CHI structures in Germany). In addition to the above general information supplied to open research registers, during observational studies, a complete list of doctors who participate in them should also be provided (the Association of Doctors also requires information on payments for filling out questionnaires). So the regulatory authorities intend to achieve full openness of observational studies and their results, preventing the use of these studies in order to promote drugs. Experts say that the fulfillment of the entire set of requirements will allow the pharmaceutical industry to regain the trust of the medical community in observational research.

Thus, today we can state a new turn in development both in the field of drug research and in the field of pharmacovigilance. At the junction of these two areas, non-interventional studies, primarily observational, receive a new impetus, but they are also subject to stricter requirements than before. This gives experts reason to hope that in the near future these studies will be perceived exactly as they should be – as a necessary tool for obtaining important information about medicinal products, which will make pharmacotherapy even more effective and safe. And gradually databases will be formed on the basis of which regulatory authorities and experts will be able to reasonably identify medicines whose use is associated with known risks, warn doctors and the public about these risks and, if necessary, take measures to limit the turnover of unsafe drugs.

Portal "Eternal youth" http://vechnayamolodost.ru17.11.2009