An audit of consent refusals in clinical research at a tertiary care center in India

Background and Rationale:

Ensuring research participants’ autonomy is one of the core ethical obligations of researchers. This fundamental principle confers on every participant the right to refuse to take part in clinical research, and the measure of the number of consent refusals could be an important metric to evaluate the quality of the informed consent process. This audit examined consent refusals among Indian participants in clinical studies done at our center.

Materials and Methods:

The number of consent refusals and their reasons in 10 studies done at our center over a 5-year period were assessed. The studies were classified by the authors according to the type of participant (healthy vs patients), type of sponsor (investigator-initiated vs pharmaceutical industry), type of study (observational vs interventional), level of risk [based on the Indian Council of Medical Research (ICMR) “Ethical Guidelines for Biomedical Research on Human Participants”], available knowledge of the intervention being studied, and each patient''s disease condition.

Results:

The overall consent refusal rate was 21%. This rate was higher among patient participants [23.8% vs. healthy people (14.9%); P = 0.002], in interventional studies [33.6% vs observational studies (7.5%); P < 0.0001], in pharmaceutical industry-sponsored studies [34.7% vs investigator-initiated studies (7.2%); P < 0.0001], and in studies with greater risk (P < 0.0001). The most common reasons for consent refusals were multiple blood collections (28%), inability to comply with the study protocol (20%), and the risks involved (20%).

Conclusion:

Our audit suggests the adequacy and reasonable quality of the informed consent process using consent refusals as a metric.KEY WORDS: Autonomy, consent, India, reason, refusal, risk     

Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease

Infusions of large numbers (> 10(8)/kg) of donor leukocytes can induce remissions in patients with chronic myeloid leukemia (CML) who relapse after marrow transplantation. We wanted to determine if substantially lower numbers of donor leukocytes could induce remissions and, if so, whether this would reduce the 90% incidence of graft-versus-host disease (GVHD) associated with this therapy. Twenty-two patients with relapsed CML were studied: 2 in molecular relapse, 6 in cytogenetic relapse, 10 in chronic phase, and 4 in accelerated phase. Each patient received escalating doses of donor leukocytes at 4- to 33-week intervals. Leukocyte doses were calculated as T cells per kilogram of recipient weight. There were 8 dose levels between 1 x 10(5) and 5 x 10(8). Lineage-specific chimerism and residual leukemia detection were assessed using sensitive polymerase chain reaction (PCR) methodologies. Nineteen of the 22 patients achieved remission. Remissions were achieved at the following T-cell doses: 1 x 10(7) (n = 8), 5 x 10(7) (n = 4), 1 x 10(8) (n = 3), and 5 x 10(8) (n = 4). To date, 15 of the 17 evaluable patients have become BCR-ABL negative by PCR. The incidence of GVHD was correlated with the dose of T cells administered. Only 1 of the 8 patients who achieved remission at a T-cell dose of 1 x 10(7)/kg developed GVHD, whereas this complication developed in 8 of the 11 responders who received a T-cell dose of > or = 5 x 10(7)/kg. Three patients died in remission, 1 secondary to marrow aplasia, 1 of respiratory failure and 1 of complications of chronic GVHD. Sixteen patients who were mixed T-cell chimeras before treatment became full donor T-cell chimeras at the time of remission. Donor leukocytes with a T-cell content as low as 1 x 10(7)/kg can result in complete donor chimerism together with a potent graft-versus-leukemia (GVL) effect. The dose of donor leukocytes or T cells used may be important in determining both the GVL response and the incidence of GVHD. In many patients, this potent GVL effect can occur in the absence of clinical GVHD.     

Blood pressure response of nephrectomized subjects and patients with essential hypertension to ramipril: indirect evidence that inhibition of tissue angiotensin converting enzyme is important

The kinetics of blood pressure changes and plasma angiotensin converting enzyme (ACE) inhibition in response to ramipril (HOE 498), 10 mg orally, were studied in 6 nephrectomized subjects 12 hours after ultrafiltration and in 10 patients with essential hypertension. Ramipril lowered supine and standing blood pressure in both groups, but the effect was greater in essential hypertension. The maximal blood pressure response followed the effect on plasma ACE after a lag time of 3 to 4 hours in both groups. These data provide indirect evidence that ramipril lowers blood pressure, at least in part, independently of its effect on the circulating renin-angiotensin system, possibly by acting on tissue ACE.     

Is beta 1-antagonism essential for the antihypertensive action of beta-blockers?

Both nonselective beta-blockers and beta 1-selective blockers are effective antihypertensive agents. beta 1-Blockade generally is considered to be responsible for their antihypertensive action, whereas beta 2-blockade is regarded as undesirable. These common assumptions notwithstanding, the mechanism by which beta-blockers lower blood pressure remains unknown. To examine the possibility that beta 2-blockade may contribute to the antihypertensive action of beta-blocker therapy, we studied the cardiovascular effects of compound ICI 118551, a beta 2-selective blocker. First, we showed that 50 mg t.i.d. orally is a beta 2-selective dose. In contrast to propranolol, 80 mg t.i.d., or atenolol, 100 mg once a day, 50 mg of ICI 118551 t.i.d. failed to block beta 1-mediated inotropic stimulation and stimulation of renin by isoproterenol. We then performed a double-blind, placebo-controlled trial in patients with mild essential hypertension to compare this compound with propranolol, 80 mg t.i.d., and showed that ICI 118551 significantly decreased systolic and diastolic blood pressure. This antihypertensive effect was demonstrated by direct as well as by indirect blood pressure measurements. Thus, contrary to prevailing thought, beta 2-blockade has an antihypertensive effect independent of, and distinct from, beta 1-blockade.     

三七中人参三醇甙对羊心浦氏纤维动作电位及延迟整流钾电流的影响

三七中人参三醇甙(PTS)2.5μg/ml及5.0μg/ml均能明显延长羊心浦氏纤维动作电位时程(APD)包括APD₃₀,APD₅₀,APD₉₀,对动作电位幅度(APA)无明显影响。双微电极法电压钳实验证明,PTS能明显抑制羊心浦氏纤维延迟整流钾电流(I_x)的峰值,且此种抑制作用呈时间及剂量依赖性。揭示PTS通过阻滞延迟整流钾通道而延长APD。