|Year : 2018 | Volume
| Issue : 2 | Page : 106-110
French Phase I clinical trial disaster: Issues, learning points, and potential safety measures
Harmanjit Singh1, Sudhir Chandra Sarangi2, Yogendra Kumar Gupta2
1 Department of Pharmacology, Government Medical College and Hospital, Chandigarh, India
2 Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||20-Jun-2018|
Yogendra Kumar Gupta
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Phase I clinical trial is the first exposure of investigational medicinal product in humans and it sets the pillar for further clinical development. Substantial attention has been paid to the first in human clinical trials after TeGenero TGN1412 disaster in 2006 which led to serious toxicity including multi-organ failure in 6 healthy volunteers. Since then many recommendation and guidelines have been formulated for the safe and rational conduct of such trials. In January 2016, another catastrophe occurred in France during Phase I trial of BIA 10-2474, a fatty acid amide hydrolase inhibitor, which led to one death and caused serious neurological damage in few other healthy volunteers. This review will focus on potential issues in BIA 10-2474 trial, possible measures that should have been taken during trials to prevent this disaster and potential safety measures for the rational and safe conduct of Phase I trials.
Keywords: BIA 10-2474, Phase I, serious adverse event, TGN1412
|How to cite this article:|
Singh H, Sarangi SC, Gupta YK. French Phase I clinical trial disaster: Issues, learning points, and potential safety measures. J Nat Sc Biol Med 2018;9:106-10
|How to cite this URL:|
Singh H, Sarangi SC, Gupta YK. French Phase I clinical trial disaster: Issues, learning points, and potential safety measures. J Nat Sc Biol Med [serial online] 2018 [cited 2020 Jun 1];9:106-10. Available from: http://www.jnsbm.org/text.asp?2018/9/2/106/234704
| Introduction|| |
Phase I clinical trial is the first application of a new chemical entity (NCE) in humans and is the foundation of a successful clinical drug development process. Carefully and rationally designed Phase I trials are essential for the further drug development process. The main goals of a Phase I trial are to explore the safety, pharmacokinetics, maximum tolerated dose and if possible, pharmacodynamics (PD) profile of the new drug.
According to a study published in British Medical Journal in 2015, in which the authors looked in WHO's international clinical trials registry platform (ICTRP) for trials that were registered between 2005 and 2013, Phase I trials comprise of only 9%–10% of the all clinical trials.
Phase I is an important milestone on which rest of the drug development process is dependent. At this stage, only preclinical data serve as a guide for dose-selection, study design, safety monitoring and appropriate expertise critical to maximize the safety of the trial participants. About 20%–40% of Phase I trials fail in further development because of safety issues.,
Substantial attention has been paid to the first in human (FIH) clinical trials after TeGenero TGN1412 disaster in 2006 which led to serious toxicity including multi-organ failure in 6 healthy volunteers. Since then various recommendations and guidelines have been laid by the different authorities.,, The European Medicines Agency's (EMA) “Guideline on strategies to identify and mitigate risks for FIH clinical trials with Investigational Medicinal Products” is an important document in this context. Healthy volunteers are employed in most of FIH studies as they can generally tolerate more intensive interventions and adverse effects as compared to diseased individuals.,
Unfortunately, almost after 10 years of TGN1412 Phase I disaster, another catastrophe occurred in France during Phase I trial of BIA 10-2474, a fatty acid amide hydrolase (FAAH) inhibitor, leaving 1 healthy volunteer dead, and 4 others seriously injured. This review will focus on potential issues in BIA 10-2474 trial, possible measures that should have been taken during trials to prevent this disaster and potential future steps for the rational and safe conduct of Phase I trials.
| Briefly about the Trial|| |
This Phase I trial titled “A double-blind, randomized, placebo-controlled, combined single, and multiple ascending dose (MAD) study including food interaction (FI), to investigate the safety, tolerability, pharmacokinetic, and pharmacodynamic profi le of BIA 10-2474, in healthy volunteers” was being conducted by the contract research organization, Biotrial in Rennes, France on behalf of the Portuguese pharmaceutical company Bial Portela. The trial was approved by the French National Agency for Medicines and Health Products Safety (ANSM) and a local institutional review board. No details of the study protocol or any other study document was revealed by the Bial citing French laws related to of trade secrets. Later, a French newspaper followed by the ANSM published a copy of the protocol of this trial.,,,
The trial was designed to enroll 128 healthy volunteers (aged 18–55 years) out of which 90 people were to receive the investigational drug, and the remainder a placebo. This trial was designed to include the following four parts:
- A single ascending dose part comprising 8 cohorts of 8 healthy volunteers receiving a single-oral dose of BIA 10-2474 (6 subjects) or placebo (2 subjects)
- A FI part consisting of 12 healthy volunteers, each receiving either a single or multiple dose of BIA 10-2474 in either the fed or fasting state in an open-label, two-way crossover design
- A MAD part comprising of 4 cohorts of 8 healthy volunteers receiving an oral dose of BIA 10-2474 (6 subjects) or placebo (2 subjects) once daily for 10 days
- PD Part comprising of 1 cohort of 20 healthy male volunteers in a double-blind, placebo-controlled, cross-over design to assess PD effects of BIA 10-2474.
The distribution of healthy volunteers was as follows: 64 in the SAD part, 32 in the MAD part, 12 in the FI part, and 20 in the PD part.
On the basis of preclinical studies, the starting dose of 0.25 mg was to be given to the 1st cohort in SAD part followed by 1.25 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg, and 100 mg in the next cohorts. The human equivalent dose of 100 mg was decided on the basis of no observable adverse effect level (NOAEL) of the rat. The duration of this Phase I trial was 13 months.
| BIA 10-2474|| |
Endogenous cannabinoids such as anandamide are one of the substrates of FAAH. BIA 10-2474 potentiates the levels of anandamide and other endogenous cannabinoids by inhibiting FAAH enzyme. BIA 10-2474 was being developed as a therapeutic modality for a variety of conditions involving endocannabinoids, for example, pain due to multiple sclerosis, cancer, anxiety, and movement disorders associated with neurodegenerative diseases. BIA 10-2474 was identified as a long-acting FAAH inhibitor on the basis of preclinical studies.,,
| Brief Description of the Adverse Event|| |
After completion of 4th cohort (20 mg/day) of the MAD study, 5th cohort of 50 mg/day dose was started on January 6, 2016. Serious adverse events (SAE) emerged in this 5th cohort. There was minimal gap (10 min) between the start of dose in 1st subject and rest of the subjects of the group. On 5th day of dosing (January 10, 2016), the first subject fell ill and was hospitalized on the same day with the symptoms similar to stroke. Later on, it was revealed that the subject developed mild symptoms on January 7, 2016, but his condition deteriorated on January 10, 2016., Even after this, the scheduled doses were given to the other study subjects of the group on the morning of January 11, 2016, at 8:00 am and the trial was suspended later that day. First subject went into coma and was declared dead on January 17, 2016., Four subjects in the same cohort were also hospitalized between 10th and 13th January, 2016, with the similar complaints. The opinion of the treating neurologist was that in 3 of the 4 men who had toxicity, the condition is such that an irreversible handicap is likely to occur despite of the institution of best possible treatment. All these patients had hemorrhagic and necrotic lesions as seen on brain magnetic resonance imaging (MRI). Sixth subject from the same cohort did not show any signs of toxicity and was discharged from the hospital.,,, Before this, the SAD part, FI part and the first 4 dose groups of the MAD part were already completed without any SAE.
| Potential Issues with This Trial and Possible Reasons for Serious Adverse Event|| |
Details of the results of preclinical and Phase I part were not available. The trial was not found in any of the clinical trials registries. Therefore, it is difficult to reach at particular conclusion regarding what had exactly gone wrong in this trial leading to this disaster. Brief information was available from the released protocol and rest is the speculations made by the field experts raising concerns with the study drug and study design.,,,
No information is available regarding the calculations of receptor occupancy, ligand binding, target affinity and compound's activity and interaction with other receptors/proteins. This information is important for predicting the possible toxicity of the compound. Although extensive detail about the study design is included in clinical trial protocol, minimal information is provided about the MAD part during which the disaster occurred.
| Lead from the Computed Structure of BIA10-2474|| |
After evaluation of the computed structure of this compound, chemists have raised concerns about the selectivity of BIA 10-2474 for FAAH. After running the structure in software programs experts have said that “the compound looks pretty dirty”.
| Potential Off-Target Effects|| |
Computed structure analysis revealed that BIA 10-2474 also acts on proteins this may explain the potential mechanism of toxicity. Apart from FAAH, other targets were also highly rated for this compound. It has shown activity against histone deacetylases, which regulate gene transcription and macrophage stimulating protein receptor, which can lead to immunological reactions and can compromise the immunity. This may give an idea about potential off-target effects of the drug.
Wide potential therapeutic roles of FAAH inhibitors, ranging from Alzheimer's disease, Parkinson's and traumatic brain injury, anxiety, nausea and vomiting, and variety of pain conditions,, may also explain that their targets are widespread. FAAH is a nonspecific enzyme, and along with endocannabinoids, it has other substrates including oleoylethanolamide and palmitoylethanolamide. MK-4409, PF-04457845, and V1158866 are other FAAH inhibitors which were tested for different indications, but they were shown to be ineffective. None of the above compounds have shown SAE in humans (lack of efficacy was the reason for their discontinuation), raising the possibility that the BIA 10-2474 might have hit the wrong target.,
Following this tragedy, Jansen Research and Development had voluntarily suspended the further development of their investigational FAAH inhibitor JNJ-42165279 (in two Phase II trials). The company announced that they are suspending these trials as a precautionary measure and none of the subjects had shown serious toxicity. According to chemists JNJ-42165279 is far more specific for FAAH as compared to BIA 10-2474 which further points toward the off-target actions of BIA 10-2474.,
| Clues from Molecule Structure|| |
Chemical structure may be useful in knowing the potential mechanism of toxicity. Bial disclosed merely the codename of this compound without revealing the chemical structure. Experts have pointed out that BIA 10-2474 might covalently bind to another molecule, leading to formation of an adduct. Adducts are recognized as foreign substances by immune system and can lead to immunological reaction and massive inflammation. The predicted molecular structure for BIA 10-2474 revealed the presence of pyridine oxide, which is a reactive molecule. However, there is no concrete evidence and these theories need experimental verification.,
| Dosing Intervals in Multiple Ascending Dose Part of Trial|| |
The clinical trial protocol does not clarify regarding any interval to be given between the dosing of subject within the same cohort and it seems that all 6 subjects received the 50 mg dose at the same time., Such dosing intervals are important to watch for occurrence of any toxicity before giving doses to the next subjects in the cohort. Dosing intervals are also recommended by the EMA guidelines  and club Phase I recommendations , which were formulated after the TGN1412 disaster. This was an important lesson learnt from TGN1412 disaster where all 6 subjects were also dosed at the same time and it seems that same mistake has been repeated by investigators in BIA 10-2474 trial.
| Was Revised Consent Needed?|| |
SAE appeared in 1st subject on January 7, 2016, and he fell seriously ill on January 10, 2016, following which he was hospitalized. Other subjects were given the test drug on the morning of January 11, 2016. At this stage, it was important to inform the other subjects regarding the toxicity which occurred in first subject to give them the chance to withdraw their consent. Therefore, revised consent should have been taken before exposing the remaining subject to the drug which already led to serious toxicity in other subject, but it seems that study investigators failed to follow such a crucial step.,
| Learning Points and Precautions for Safe Conduct of Phase I Trials|| |
TGN1412 disaster was a sole example of a drug development program failure which left sponsors, investigators, a clinical research organization, participants, and regulators shocking. The investigator brochure highlighted very small risk of developing a cytokine storm based on the results of TGN1412 testing in nonhuman primates but when TGN1412 was tested in Phase I clinical trial, it was immediately withdrawn because it led to massive cytokine storm and 6 volunteers had to be taken to intensive care unit 8 h after drug infusion due to multiorgan failure. After this catastrophe, many authorities worked and laid down stringent rules and guidelines for the safe conduct of Phase I trials. BIA 10-2474 tragedy is the second such unfortunate event demanding detailed investigation and further amendment in the existing rules and regulations.
In general, following points and future steps should be considered.
- Careful screening and evaluation of investigational compounds for their on and off-target effects is important to know the potential and expected AEs. This will also help in better management of anticipated toxicity
- Careful selection of preclinical models including relevant species and correct interpretation of preclinical toxicity data is needed. In TGN1412 trial, cytokine release was also observed during the preclinical toxicity studies, but investigators might have ignored and let it go without expecting this to happen in humans. Concerns have been raised that BIA 10-2474 led to serious toxicity and deaths in preclinical toxicology study part in dogs , but whether this is related to the SAE in human subjects or not is not yet clear
- Careful selection of starting dose is important as minor errors in calculation of starting dose based on predicted NOAEL may prove dangerously wrong
- Execution of dosing intervals between the dosing of one subject and the other is a key step as this helps researchers to watch for possible toxicity in one subject before other subjects being exposed to the drug, therefore protecting next subjects. If such a plan was executed in this Phase I trial, toxicity could have been prevented in the 4 other subjects
- Implementation of stringent stopping rules is important. The EMA recommendations on risk management include a risk minimization strategy based on clearly defined stopping rules. Club Phase I working group also proposed a safety grading system that might help in rationalizing dose escalation and stopping decisions
- More transparency in NCE structure, preclinical data publication and accountability regarding the ethical conduct of the trial is crucial. Timely information of any AE to other study subjects and consideration of revised consent before giving them further doses could avoid toxicity in other subjects. Adequate plan, for tackling AEs where there is a known theoretical risk, is needed. Any anticipated toxicity should not be ignored, and all measures should be kept ready to deal with the same
- During the conduct of Phase I trials, stringent monitoring and inspection should be mandatory by clinical trial monitors, Ethics Committees and Regulators
- Micrdosing or Phase 0 studies can be employed before Phase I to explore certain aspects of the drug effects. The role of microdosing is now expanding (initially designed for purely pharmacokinetic prediction), for example, to predict the levels of a drug in cell or tissue types (could be helpful in predicting tissues/organs likely to be affected by the drug toxicity), drug-drug interactions before and after the administration of a drug known to inhibit or induce cytochrome P450 system and obtaining Information regarding the metabolism of a drug candidate by administering a carbon-14 labeled and comparing the plasma concentration-time curves to the parent compound.
| Clinical Trial Regulations: Implications for India|| |
No such Phase I tragedy has ever happened in India, though unethical concerns have been raised for few later stage trials. There were some controversies in previous years, for example, clinical trial without informed consent, human studies without adequate safety studies in animals, conduct of Phase III trial without completion of Phase II, stopping standard treatment and replacing it with placebo and so on. Therefore, considering patient safety as paramount, the Indian Government has updated various guidelines and policies regarding the conduct of clinical trials, for example, compensation in clinical trials in case of SAE including death (highest in case of healthy volunteers), registration of ethics committees, audiovisual informed consent process, requirement of timely reporting of SAE, transparency in the form of compulsory registration of trials with Clinical Trial Registry of India.,,,, These stringent rules demand a high level of ethical and scientific conduct of clinical trials in Indian set up, and this may help in avoiding such serious events.
| Conclusion|| |
Careful, rational, and ethical approach should be adopted for the successful conduct of the Phase I studies. Investigators should not ignore even the minor leads from the preclinical toxicity studies to avoid the major mishaps.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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