A clinical trial is a prospective study designed to establish the safety and efficacy of investigational devices in humans, in accordance with the strict guidelines of the Food and Drug Administration (FDA; USA) or European Medicines Agency (EMA; Europe).
Before a clinical first-in-human study is initiated, preclinical studies of the investigational product are mandatory, and the results should be sufficient to indicate that the investigational device is acceptably safe for the proposed evaluation in human subjects.
The present paper describes an experience of clinical trials, highlighting ways of avoiding possible complications in clinical first-in-human studies. For a better approach to our aim, we exemplified a prospective, randomized, single-blind study, ADBEE. The primary objective was to assess the safety of the ADBLOCK system when used as an adjunct to laparoscopic primary removal of myomas in women wishing to improve pregnancy outcomes.
Highlights
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Our experience of clinical trials, highlighting ways of avoiding possible complications in clinical first-in-human studies.
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We exemplified a prospective, randomized, single-blind study, ADBEE, carried out in three different centers in Germany.
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Preclinical studies for ADBEE provided evidence of safety and efficacy of the ADBLOCK reducing adhesions in animal models.
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The first-in-human clinical trial of the ADBEE study has reached its end point in terms of safety.
Introduction
The clinical trials are conducted in a series of stages, called phases, with each phase being designed to answer a separate research aspect.
I. Preclinical, nonclinical studies. These include studies with a duration of 2–3 years on different models such as cultured tissue and animals. The safety examination includes the study of toxicology, pharmacology, biochemistry, mutagenicity, and pharmacokinetics (absorption, drug distribution, metabolism, and excretion). For the first-in-human studies, the early nonclinical examinations should provide sufficient information on the initial human dose and safe duration of exposure as well as produce data on the physiological and toxicological effects of the investigational device .
Preclinical phase for ADBLOCK System
Preclinical studies for ADBEE were undertaken in accordance with standards issued by the International Organization for Standardization (ISO), harmonized European standards (EN) , and the Food and Drug Administration (FDA) Guidance for Resorbable Adhesions Barrier Devices (FDA, US Food and Drug) . These studies have provided evidence of both the safety and efficacy of the ADBLOCK system in reducing adhesions in standard animal models . Although novel compounds, the constituent elements are well-established agents for use in clinical practice.
The safety and efficacy of ADBLOCK is based on the results obtained from the biocompatibility and pharmacokinetic studies, in vitro testing, manufacturing and control data, in vivo testing, sterilization validation, and stability testing. A comprehensive risk review for ADBLOCK has also been performed in accordance with EN ISO 14971. The details of the risk management review are described in a risk management report. This concluded that all known possible risks associated with the materials, design, manufacturing process, and clinical use of the system have been considered and made acceptable by taking into account requirements stipulated in applicable harmonized standards or international standards during design, production, and testing, or by putting in place the necessary precautions, warnings, or contraindications in the information provided with the device.
Biochemical safety
ADBLOCK Adhesion Barrier is an experimental site-specific sprayable adhesion barrier gel based on a dextrin polymer, which is currently being investigated as an adhesion-reducing agent for use in patients undergoing abdominopelvic surgery as an adjunct to surgery, with the aim of reducing the incidence, severity, and extent of adhesion formation postoperatively.
A similar existing dextrin polymer (icodextrin) has recently been approved in Europe and the USA as an anti-adhesion solution (Adept ® ), with an excellent long-term safety record from its global use as an intraperitoneal dialysate as well as an anti-adhesion agent. The anti-adhesion solution Adept is currently the most widely used anti-adhesion agent available. Although it has been shown to be safe and effective in reducing adhesions , recent research suggests other advantages offered by site-specific gels such as ADBLOCK .
The polymer system in ADBLOCK is a novel compound based on existing and established agents. It contains one precursor comprising an NHS (N-hydroxysuccinimide)-modified carboxymethyl dextrin polymer with trehalose (alpha linked disaccharide), which has been used in various pharmaceutical biopharmaceutical agents (including the monoclonal antibody formulations trastuzumab and bevacizumab – Herceptin ® and Avastin ® ) and is being investigated for its anti-adhesion potential in ocular surgery. The other precursor is a standard alkaline sodium hydrogen carbonate/sodium carbonate (NaHCO 3 /Na 2 CO 3 ) buffer agent. When sprayed together, the dextrin polymers link to form a hydrogel barrier within 10 s, a hydrogel predominantly of dextrin polymers and microbubbles consisting of 60–95% water with solids ( Fig. 1 ). These microbubbles within the gel provide an opaqueness that allows easier visualization of the gel placement, thickness, and coverage. This formulation may have advantages over some other available gel agents that require the use of colorants for visualization as well as reformulation due to issues of tissue reactogenicity .
The dextrin-based polymer gel has good adherent properties when sprayed on tissues, providing a temporary barrier that prevents fibrin deposits from the damaged mesothelium from forming a bridge and interconnecting the opposing tissue surfaces ( Fig. 2 ).
A pharmacokinetic study on a radiolabelled product in a rabbit model showed that the ADBLOCK gel remained visibly in the abdominal cavity about 1 day after spraying into the rabbit abdominal cavity and was absorbed from the abdominal cavity within 3 days after spraying. This short residence time not only provides coverage during the critical period of adhesion formation but also ensures the agent is not retained after this period, similar to other agents . The agent is removed from the abdominal cavity through the lymphatic system and absorbed into the bloodstream where it is hydrolyzed by the enzyme amylase and then cleared through the kidneys.
II. Clinical studies. During research, three ethical principles should be respected: the safety of the human subjects, obligation to do no harm with minimum injuries for the patients, and an equitable proportion of advantages and disadvantages of the research. The principles for protecting human subjects, which represent an essential requirement for clinical trials, originate from the Declaration of Helsinki, and they should be strictly followed when conducting product investigations in humans .
The clinical development of an investigational device involves the following four temporal phases:
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Phase I (human pharmacology): This phase begins with the initial use of the investigational product in human subjects, involving one or a combination of the following: estimation of initial safety and tolerability, pharmacokinetics, pharmacodynamics, and early measurement of drug action.
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Phase II (therapeutic exploratory): The primary objective of this phase is to explore the therapeutic efficacy in patients.
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Phase III (therapeutic confirmatory): The primary aim of this phase is to demonstrate or confirm the therapeutic benefits of the investigational device.
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Phase IV (therapeutic use): This phase begins after the investigational device is approved .
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The safety of clinical trial subjects
According to International Conference on Harmonisation-Good Clinical Practice Guidelines and ISO 14155, all clinical studies should be monitored with the aim of protecting patients from preventable harm. The safety monitoring is directed toward the early detection and prevention of rare, severe adverse reactions . Clinical investigators are required to report all serious adverse events (SAEs) to the sponsor, regardless of being device related.
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Adverse event (adverse experience)
An adverse event (AE) is any undesirable experience (sign, symptom, illness, abnormal laboratory value, or other medical event) of a patient that appears or worsens during the study, regardless of its relation to the product being studied or drug regimen prescribed as part of the clinical investigational plan. Failure of the device may be considered an AE if an undesirable experience occurs. The clinical investigators are required to report the AEs to the sponsor as soon as possible without unjustifiable delay. The investigator should record the nature, severity, treatment, and outcome of the AE, as well as determine the event’s relationship to the investigational products.
The severity of each AE can be defined as follows:
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Mild: This constitutes awareness of a sign or symptom that does not interfere with the patient’s usual activity or is transient, which is resolved without treatment and presents no sequelae.
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Moderate: This interferes with the patient’s usual activity and/or requires symptomatic treatment.
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Severe: This includes symptom(s) causing severe discomfort and significantly affecting the patient’s usual activity, requiring treatment.
The relationship of the AE to the use of the studied product/device can be defined as follows:
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Not related: The event is definitely not associated with the drug or device application. The AE is due to an underlying or concurrent illness or the effect of another device or drug.
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Unlikely: An AE has little or no temporal relationship to the study device and/or a more likely alternative etiology exists.
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Possible: The temporal sequence between drug or device application and the event likely point to their relationship, or the patient’s condition or concomitant therapy could have caused the AE.
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Probable: The temporal sequence is relevant or the event declines upon completion/removal of the device application or the event cannot be reasonably explained by the patient’s condition.
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Highly probable: The temporal sequence is relevant and the event declines upon completion of the device application, or the event reappears when device application is repeated.
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Serious adverse event
For each AE observed, the investigator must determine whether the event meets the definition of a “serious” adverse event (SAE). An event is considered serious under the following conditions:
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Death
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A serious deterioration in the health of the subject that
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resulted in a life-threatening illness or injury
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resulted in permanent impairment of a body structure or a body function
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required patient hospitalization or prolongation of existing hospitalization
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resulted in medical or surgical intervention to prevent permanent impairment to body structure or a body function
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Fetal distress, fetal death, or a congenital abnormality or birth defect.
The clinical investigators should report all SAEs to the sponsor as soon as possible without unjustifiable delay.
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Device malfunction
A device malfunction is defined by the failure of a device to meet its performance specifications or a performance contrary to the labeled indication. In the case of failure of a device, the investigator must return the device to the sponsor.
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Unanticipated serious adverse device effects
An unanticipated serious adverse device effect is defined as an effect that has not been identified by its nature, incidence, severity, or outcome in the clinical investigational plan accompanying the risk analysis report. Sites are requested to report promptly any device malfunction and unanticipated adverse device effect.
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Outcome categorization
Outcomes may be classified as resolved, unresolved, resolving, resolved with sequelae, death, or unknown.
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ADBLOCK system in first-in-human clinical trial (phase I)
Material and methods
A first-in-human clinical trial based on a randomized, controlled multicentric study was conducted to assess the safety, manageability, and usability of the ADBLOCK system when used as an adjunct to laparoscopic surgery for the primary removal of myomas in women wishing to improve pregnancy outcomes. The study was carried out in three different centers in Germany: University Hospital for Gynecology, Pius-Hospital Oldenburg; Department of Obstetrics and Gynecology at Johanna-Etienne-Clinic, Neuss; and the Clinic for Minimal Invasive Surgery, Berlin-Zehlendorf, Germany.
The study involved single-blind subjects, and the investigators were blinded to the assignment of treatment groups until completion of uterine suturing and prior to removal of the endoscope.
Participants: Preoperatively, the patients met the following inclusion criteria: generally healthy women aged between 18 and 45 years with negative pregnancy test results before entry into the study, who have not completed their childbearing and who are undergoing primary (“virgin”) laparoscopic myomectomy with the aim of improving pregnancy outcomes. The patients provided voluntary written informed consent and were willing to use adequate forms of contraception for 12 weeks following the surgery. The pre- and intraoperative exclusion criteria were as follows: use of gonadotropin-releasing hormone (GnRH) agonist/antagonist treatment in the 4 weeks prior to the study, breast-feeding, previous bowel surgery, pelvic malignancy, pelvic inflammatory disease, an immunocompromised condition, or intraoperative use of corticosteroids. Patients requiring a conversion to laparotomy or any unplanned surgery with opening of the bowel or urinary tract intraoperatively and patients with extensive pelvic adhesions (AFS severe adhesion score) or frozen pelvis were excluded.
Study design: The patients were randomized into two groups: the ADBLOCK arm with 21 patients and the surgery-only arm with 11 patients. As a primary end point, the safety was evaluated by assessing the AEs in the ADBLOCK and surgery-only groups up to 28 days to confirm that the use of ADBLOCK is as safe as surgery alone. The manageability and usability of the device were analyzed as secondary end points of the study ( Fig. 3 ).
The study flow is represented in Figs. 4 and 5 .
Material and methods
A first-in-human clinical trial based on a randomized, controlled multicentric study was conducted to assess the safety, manageability, and usability of the ADBLOCK system when used as an adjunct to laparoscopic surgery for the primary removal of myomas in women wishing to improve pregnancy outcomes. The study was carried out in three different centers in Germany: University Hospital for Gynecology, Pius-Hospital Oldenburg; Department of Obstetrics and Gynecology at Johanna-Etienne-Clinic, Neuss; and the Clinic for Minimal Invasive Surgery, Berlin-Zehlendorf, Germany.
The study involved single-blind subjects, and the investigators were blinded to the assignment of treatment groups until completion of uterine suturing and prior to removal of the endoscope.
Participants: Preoperatively, the patients met the following inclusion criteria: generally healthy women aged between 18 and 45 years with negative pregnancy test results before entry into the study, who have not completed their childbearing and who are undergoing primary (“virgin”) laparoscopic myomectomy with the aim of improving pregnancy outcomes. The patients provided voluntary written informed consent and were willing to use adequate forms of contraception for 12 weeks following the surgery. The pre- and intraoperative exclusion criteria were as follows: use of gonadotropin-releasing hormone (GnRH) agonist/antagonist treatment in the 4 weeks prior to the study, breast-feeding, previous bowel surgery, pelvic malignancy, pelvic inflammatory disease, an immunocompromised condition, or intraoperative use of corticosteroids. Patients requiring a conversion to laparotomy or any unplanned surgery with opening of the bowel or urinary tract intraoperatively and patients with extensive pelvic adhesions (AFS severe adhesion score) or frozen pelvis were excluded.
Study design: The patients were randomized into two groups: the ADBLOCK arm with 21 patients and the surgery-only arm with 11 patients. As a primary end point, the safety was evaluated by assessing the AEs in the ADBLOCK and surgery-only groups up to 28 days to confirm that the use of ADBLOCK is as safe as surgery alone. The manageability and usability of the device were analyzed as secondary end points of the study ( Fig. 3 ).
