Communicated on 18 September 2017
THIRD SECTION
Application no. 21648/11
Nonna Vladimirovna TRASKUNOVA
against Russia
lodged on 17 March 2011
STATEMENT OF FACTS
The applicant, Ms Nonna Vladimirovna Traskunova, is a Russian national who was born in 1925 and lives in St Petersburg. She is represented before the Court by Mr V. Lapinskiy, a lawyer practising in St Petersburg.
A. The circumstances of the case
The facts of the case, as submitted by the applicant, may be summarised as follows.
The applicant is the mother of A.T., born in 1947 but now deceased. In 1964 A.T. was diagnosed with schizophrenia. She had treatment for that condition at various psychiatric hospitals and as an outpatient until her death. A.T. retained her legal capacity.
1. Background information
On 25 February 2004 the Ethics Committee at the Federal Body for the Quality Control of Medicinal Products (“the Ethics Committee”) approved clinical trials of a drug called Org 5222 in comparison with olanzapine, in accordance with protocol no. 25517.
According to the patient information leaflet (“the leaflet”), the purpose of the trial was to test the safety and efficacy of Org 5222 (another name for asenapine) in comparison with olanzapine, widely used for the treatment of schizophrenia and similar conditions, when used for a period not exceeding one year.
The research was the third phase of trials of the drug. The number of participants was expected to be 1,200, including 200 enrolled in Russia. The trial was designed as a double-blind test.
According to the leaflet, participants needed to undergo various examinations to determine their eligibility for the trial. In particular, they were required to have a comprehensive check-up, blood tests and an electrocardiogram. Participation in the trial was subject to patients being of satisfactory health.
The leaflet included information about the procedures for following up on patients’ health and on gathering data about the effects of the drug. Regular visits to the doctor leading the study were envisaged. During the visits, the doctor would monitor vital signs, check motor function, and ask questions concerning possible side effects. Measurement of the electrical activity of the heart (an ECG) would be performed at six of the visits, and general blood tests carried out at ten of them.
As regards the risks involved in connection with the trial and possible side effects, the leaflet contained a warning that the side effects of all experimental products were unforeseeable and that comprehensive information about the effects on humans of the product being tested was not yet available. With reference to previous clinical tests, the leaflet stated that the most common side effects of Org 5222 had been sleepiness, headaches and insomnia. The side effects of olanzapine had been constipation, sleepiness, weight gain, dizziness, and agitation. It could also cause neuroleptic syndrome and tardive dyskinesia.
Any participant experiencing side effects would have the dose changed by the doctor. If significant side effects remained for a long time, the doctor in charge could exclude the participant from the trial. Participants could discontinue treatment at any time on their own initiative.
The doctor in charge was required to estimate the degree of risk in respect of each participant. If the degree of risk became intolerable from the medical point of view, the doctor would inform the person concerned either before or during the trial.
The period of the trial was limited to one year. If during that time new information became available that was capable of affecting a participant’s wish to continue treatment, the doctor would inform the participant of that data and ask the person to confirm their intention to continue the trial.
Participants would only learn which of the two drugs they had been taking when the analysis of the data collected during the trial had been completed.
On 24 May 2004 the Department for State Control of Medicinal Products, Goods and Devices at the Ministry of Health of Russia allowed eighteen hospitals in various regions of the country to conduct clinical trials of Org 5222. The list included Municipal Psychiatric Hospital no. 3 in St Petersburg (“the psychiatric hospital”).
On 22 March 2005 the Ethics Committee approved a clinical trial of asenapine (Org 5222) in comparison with olanzapine for long-term treatment (protocol no. 25520).
The patient information leaflet in respect of that study stated that the trial aimed “to give patients who had successfully participated in the previous trial an opportunity to continue treatment”. The trial was planned for “no less than one year”. It was to be discontinued if necessary for administrative reasons or for reasons of safety.
The patient information leaflet read that participants would receive the same product as in the previous trial. Information about which drug (asenapine or olanzapine) had been taken by each participant would remain secret until the relevant information on the previous trial had been disclosed.
The leaflet contained no new information concerning the risks involved for participants.
The section on procedures contained information about the required regular visits and check-ups by the doctor. Patients were to see the doctor every month during the trial, an ECG would be performed every six months and general blood tests taken every three months. The leaflet stated that admission to the trial depended on the general state of health of people who agreed to participate. The leaflet did not mention what checks of participants’ general health would be made prior to the start of the new trial.
On 31 May 2005 the psychiatric hospital was included in the list of hospitals conducting the trial in accordance with protocol no. 25520.
2. A.T.’s participation in the clinical trial of asenapine and her hospitalisation
On 19 December 2004 A.T. visited her doctor at the psychiatric hospital, who invited her to take part in the clinical trial of a new drug called asenapine. It was known that she had taken part in earlier trials and had tolerated the product well.
On the same day, A.T. signed a consent form for the trial, in accordance with protocol no. 25517. The text of the consent form read as follows:
“I hereby confirm that I have read this document and have discussed the information in it with my doctor. I have had an opportunity to ask the questions which interest me and have received answers to those questions. ... I realise that I do not lose my statutory rights of a participant in a clinical trial.
I give my consent for [the company O., the public health authorities and the ethics committee] to have access to my medical files ...
I voluntarily agree to participate in this trial. I understand that I can end my participation without providing reasons for doing so at any time. I also confirm my readiness to follow all of the doctor’s instructions. I will inform the doctor about all the relevant side effects and other medicines I am taking.”
The form also contained a statement signed by the doctor responsible for the trial. The statement read as follows:
“I hereby confirm that I have spoken to the patient ... in detail about the nature and procedures of this trial. I also confirm that the patient ... fully understands the risks and benefits in connection with his or her participation in it.”
A.T. started taking the experimental product on 27 December 2004.
According to the available medical documents, the following side effects were shown in her case: the progression of her schizophrenia, agitation, insomnia, and weight gain.
On 18 May 2005 A.T. was taken by ambulance to the psychiatric hospital as she had started feeling unwell. She remained at the hospital for treatment afterwards.
On 26 December 2005, while still at the hospital, A.T. signed a consent form to participate in the further clinical trial of asenapine, in accordance with protocol no. 25520. The consent form had the same wording as the one she had signed on 19 December 2004.
The medical documents submitted by the applicant do not give any lack information on the frequency of A.T’s examinations by the trial doctor, the results of those examinations and measurements taken during the clinical trials.
3. Events of 10-14 April 2006
On 10 April 2006 A.T. suffered cardiac and respiratory arrest. After attempts at resuscitation she was transferred to the intensive care unit. She remained in a coma until her death, which was registered on 14 April 2006.
According to an autopsy report of 17 April 2006, A.T. died as a result of cardiovascular collapse caused by a heart condition, the subsequent development of pneumonia, cerebral oedema and brain herniation.
4. Investigation into A.T.’s death
(a) Investigation by the Health Care Committee of St Petersburg Government
On 26 May 2006 the applicant applied to the Health Care Committee of St Petersburg Government (“the Health Care Committee”) in order to establish the circumstances of her daughter’s death and to identify those responsible.
On 20 September 2006 the Health Care Committee’s clinical and expert commission, having examined the case, found that the clinical trials of asenapine had been conducted in compliance with all the required conditions: the Good Clinical Practice procedures had been followed, A.T. had had indications for the drug to be prescribed, she had consented freely to taking part in the trial, and there had been no grounds to exclude her from the trial during treatment. The commission found no direct causal link between her death and the taking of asenapine.
The commission expressed the view that A.T. might have fallen into a coma on 10 April 2006 because of a pulmonary embolism. As she had been taking hepatoxic neuroleptics (that is, able to affect the liver) for many years, that could have affected her physical state. Such factors, together with vascular sclerosis, could lead to changes in the blood’s ability to clot. According to the experts, the pneumonia which had arisen during the coma could also have been a result of the pulmonary embolism. The commission concluded that there had been no failings in A.T.’s treatment at the psychiatric hospital.
(b) Preliminary police check
On 15 May 2006 the applicant wrote to the prosecutor’s office of the Primorskiy District of St Petersburg, requesting the opening of a criminal case to investigate the circumstances of A.T.’s death at the hospital. Another letter was sent on 15 August 2006 by a non-governmental organisation acting on her behalf.
(i) Expert report of 12 January 2007
On 28 December 2006 the prosecutor ordered an expert examination. The question to be addressed by the experts read as follows: “to establish whether ‘asenapine’ could provoke a heart attack with thrombosis and death”.
According to a report by the experts of 12 January 2007, there had been certain failings in the treatment of the applicant’s daughter and the conduct of the asenapine trial. In particular, the experts stated that heart and liver function should be kept under observation when such a drug was prescribed. However, the only ECG available to the experts had been dated 10 April 2006, that is when A.T. had already fallen into a coma. Moreover, in the period before her death she had been seen by doctors every third or fourth day instead of the daily check-ups required when a new medicine was being tested.
The experts noted that the asenapine trial in December 2004-2005 had revealed various negative side effects in A.T.’s case, such as a worsening of her schizophrenia, insomnia, agitation and weight gain. The clinical picture, in conjunction with the cardiotoxic effect of asenapine, could therefore have been grounds to exclude A.T. from further participation in the trial. The experts also noted that her medical documents lacked information about any checks of the patient’s cardiovascular system during the further period of the trial of asenapine.
The experts attested that A.T.’s coma on 10 April 2006 had been caused by several factors: pneumonia, which had been overlooked by the doctors; the taking of asenapine, which had had a cardiotoxic effect; and a latent cardiovascular disease (according to the autopsy findings, A.T. had had third-degree general atherosclerosis and cardiosclerosis). The experts concluded that there was therefore an indirect causal link between A.T.’s death and the taking of asenapine.
(ii) Acts of medical expert examination of 10 April 2009 and 30 December 2009
On 26 March 2009 the investigator asked for a new expert examination in the case. The experts were expected to answer, in particular, the following questions. First, whether the treatment strategy for A.T. during the clinical trials of asenapine and when trying to resuscitate her had been correct. Second, whether there was a causal link between the acts of the psychiatric hospital’s personnel (the failings identified in the expert report of 12 January 2007) and her death.
On 10 April 2009 the commission, composed of four experts, confirmed that there had been various failings in the medical services provided to A.T. during the clinical trials of asenapine. In particular, they detected a lack of general monitoring of the state of A.T.’s health; a lack of monitoring of her heart and liver function; engaging A.T. for the second round of the trial of asenapine, for which she had had no indications (“не было показано”) given the possible cardiotoxic effect of the product and the side effects A.T. had experienced during the first round of the trial; and the failure to detect her pneumonia in a timely manner. The experts pointed out that no information about A.T. having any physical or laboratory examinations (pulse, blood pressure, temperature, blood and urine tests, and so forth) could be found in her hospital records.
The experts established that there was a causal link between those failings and A.T.’s death, but that the link was indirect as they could have contributed to the worsening of A.T.’s cardiovascular and respiratory diseases, with the possibility for an adverse outcome.
On 30 December 2009, at the investigator’s request, an additional act for a medical examination was prepared. The questions remained the same, but the commission this time included five experts. They were also provided with some additional material, such as the brochures for the clinical trial of asenapine and the trial report. The additional act mentioned that an order had been inserted in one of A.T.’s medical files to remedy violations of certain licence requirements. The points of criticism in the order included, for example, the fact that of all the required specialists the patient had been seen only by a gynaecologist. Actual measurements of her blood pressure, temperature, blood and urine test results had also not been found anywhere in the medical files. The conclusions of the additional study were similar to those of the report of 10 April 2009.
(iii) Refusal to open a criminal case
On 31 December 2009, after several refusals to open a criminal case and subsequent remittals of the material used in the preliminary report for further investigation, ordered either by the prosecutor or the domestic courts, the investigator yet again refused to open a criminal case for lack of the elements of a crime in the doctors’ acts.
Relying on the testimony of the applicant and doctors, as well as the experts’ findings, the investigator concluded that there was no direct causal link between A.T.’s death and the failings attributed to the medical services that the experts had pointed out. The investigator found that both the applicant and her daughter had known that she was taking part in the trials, as confirmed by A.T.’s signature on the consent forms of 19 December 2004 and 26 December 2005.
The applicant appealed against the decision of 31 December 2009. On 13 August 2010 the first-instance court looking at the case dismissed her appeal. On 5 October 2010 the applicant’s cassation appeal was also dismissed.
B. Relevant domestic law
Decree no. 266 of the Russian Ministry of Health, dated 19 June 2003, approved the Standards for Good Clinical Practice. Those standards, as in force at the relevant time, provided as follows:
Section 1.2
“The present standards establish requirements for the planning, conducting, documenting, and monitoring of clinical trials, and are designed to guarantee the protection of the rights, safety and health care for those participating in trials ...
These standards are obligatory for all parties involved in clinical trials within the Russian Federation.”
Sections 3.1-3.3
“A person enrolled in a trial shall give his or her written consent for participating in it. Such participation is voluntary.
The participant shall be informed, inter alia, about the investigatory drug, the nature of the research, and about the expected efficacy, safety and risks for participants.
A participant can, at any stage, refuse to participate in the trial.”
Chapter IV, sections 4.1-4.9, of the standards regulated the procedure for informing a participant about the clinical trial. A written consent form was to be approved by the Ethics Committee prior to the start of any clinical trial. Information about the trial had to be delivered to potential participants in clear and understandable terms. A potential participant had to be given enough time to make a decision about whether or not to participate and had to be given access to detailed information about it.
Section 7.13
“The doctor responsible for a trial shall recruit participants who can be involved in the clinical trial of a medicinal product based on medical indications.”
Section 7.15
“The doctor heading a study can stop the clinical trial if any dangers to the health of participants have been identified during the trial.”
COMPLAINTS
The applicant complains under Article 2 of the Convention that the doctors in the present case acted in violation of the regulations for clinical trials and in breach of their duty to ensure A.T.’s safety in such clinical trials. She alleges, in particular, that the doctors put A.T.’s life at risk by their failure to monitor her condition throughout the trials, to discontinue the trial after side effects had been shown, and to keep the required medical records. The applicant alleges that her daughter was involved in one clinical trial after another without the required break and without giving her informed consent. The applicant further complains that the authorities failed to conduct an effective investigation into her allegations in respect of the above matters.
QUESTIONS TO THE PARTIES
1. Has the State complied with its positive obligation to take appropriate steps to safeguard the life of the applicant’s daughter (see Calvelli and Ciglio v. Italy [GC], no. 32967/96, ECHR 2002‑I)?
In particular:
(a) before the clinical trials of asenapine (and Org 5222), to what extent were its side effects and negative effects known to the doctors responsible for the trials?
(b) did the doctors know, and should they have known, about A.T.’s cardiovascular disease before the commencement of each of the clinical trials?
(c) was A.T.’s state of health examined prior to each of the clinical trials, as required by the protocols for clinical trials and national legislation? Did her condition each time meet the requirements for her enrolment in the trial in question?
(d) at the material time, what were the national standards and regulations governing clinical trials? In particular, what did those regulations say about following up on participants during trials, keeping medical records about them, and the intervals between clinical trials for each person? Were those and other relevant standards and procedures complied with during all the clinical trials in respect of A.T.? The Government are invited to submit supporting documents.
(e) did A.T. give her informed consent to all the clinical trials she took part in? Was she each time duly informed about all the known side effects and risks entailed for her in connection with taking of the tested product? In particular, how did the trial doctors ensure that A.T. had fully understood the information concerning the clinical trials before signing the written consent forms (see Arskaya v. Ukraine, no. 45076/05, 5 December 2013)? The Government are invited to provide details as to the circumstances and the length of the meetings between the doctors involved and A.T. which preceded the signing of the consent forms.
2. In the particular circumstances of the case, were the authorities under an obligation to open and carry out an effective criminal investigation to comply with their obligation under Article 2 of the Convention (see Mehmet Şentürk and Bekir Şentürk, no. 13423/09, ECHR 2013)? If so, did they comply with that obligation?
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