This past January, a seemingly routine phase I clinical trial in France has turned into a nightmare.
At issue is a new drug, a fatty acid amide hydrolase (FAAH) inhibitor, BA-10-2474, from Portuguese company Bial. There are other FAAH inhibitors under study by other companies in the US and abroad but the issue here relates to the Bial drug.
A clinical research organization (CRO) Biotrials in Rennes, France began a phase I study in January. The protocol, in English, was published by the French newspaper Le Figaro. See also a summary as of 5-February.
This study involved 128 healthy volunteers studying the safety and PK/PD of the drug. There were 8 separate groups with each group comprising 6 volunteers to receive the drug and 2 placebo controls. Each received a single oral dose. Group one received 0.25 mg, with increases in each group to 1.25, 2.5, 5.0, 10, 20, 40 and 100 mg. Escalation was based on the safety in the previous group.
Based on various published reports in the press and on-line, there were no safety issues in the groups until the 40 mg group, Cohort 4, (some press reports say this was a 50 mg group though the protocol says 40 mg) was dosed. That is, there were no issues reported at each dose escalation until the 40/50 mg group was reached.
The 40/50 mg group (cohort 5) was dosed on January 5, nineteen days after the 20 mg group was dosed. On January 10, five days later, one volunteer was hospitalized with severe neurologic problems. On January 11, seven others also received the 40/50 mg dose. The hospitalized patient became comatose on January 11. Five of the newly dosed subjects were hospitalized between January 13 and 15. The French Health Agency was notified on January 14 of these serious adverse events. The first patient hospitalized died. The other five are reported to be improving. The trial was stopped.
Several investigations were launched and the French Minister of Health commented at a Press Conference that the trial should have been stopped after the first person was hospitalized. She also noted that the lab should have warned the French Health Agency more quickly, though apparently they did not break any laws or regulations by notifying the agency 4 or 5 days after the events occurred. She also said the other participants in the trial should have been asked whether they wanted to continue. The results of the French Ministry’s investigation were released (in French).
Others commented also:
- The UK Royal Statistical Society noted that “there are clear statistical reservations about the study design” and called for disclosure of more information about the trial and the Investigator Brochure.
- At least one law firm also commented.
All sorts of questions and issues are now being brought up and various investigations are still underway regarding this trial specifically and similar phase I trials in general. Such questions include:
- Was all the appropriate data supplied to the French HA by Bial and Biotrial?
- How was the study managed and tracked?
- Did the two companies supply the hospital treating the six people receive all the relevant data to be able to treat them?
- Why did the companies wait four or five days to notify the French HA (even though this was not contrary to the legal and regulatory requirements)?
- What actually happened medically to the subjects? Does this have any consequences for other FAAH inhibitors undergoing clinical trials?
- What should be done at the European (EU) level? Currently a temporary scientific committee with French and European toxicologists, pharmacologists, neurologists and other clinicians is being set up to address this.
Doubtless more details, charges, accusations, etc. will come over the next several weeks to months. Nonetheless, there are several things that can be learned even at this early stage of the situation in regard to both phase I studies, other studies and post-marketing safety.
Phase I Studies – Particularly in Volunteers
When trouble comes it will often come rapidly with no warning and with a need for immediate action – particularly if the subjects are normal volunteers.
- Most phase I studies play out with minimal or no safety issues, particularly if the drug is known, has a benign safety profile to date and the subjects are healthy young male volunteers. Thus one might become complacent and not pay as much attention as one might if one were working with sick patients getting a toxic product.
- One case can matter. Usually it is hard to make a causality and safety judgment on a single case. FDA has addressed this in multiple documents. However, FDA has noted that in healthy young volunteers in short term trials (e.g. phase I) non-drug related SAEs would NOT be expected. That is, if an SAE occurs in these subjects it is likely drug related and should be presumed to be due to the drug.
So one act as though every SAE is possibly related and, if severe medically (and serious) it should be evaluated immediately and a decision made on whether to stop the study or make other changes.
- As noted, there is often no warning. In addition, as anyone who works in an Emergency Room can tell you, bad things often occur on the weekend (or during full moons!). In the Bial trial the first patient’s severe neurologic event started on a Sunday. Companies must have a 365 day, 24/7 set-up in place to evaluate safety issues and empowered and ready to act immediately. In-patient observation for phase I studies is often preferred even if no issues are expected.
- It may be necessary to break the blind immediately for patient treatment and protocol change evaluations. A mechanism should be set up for this which will protect the patient/subject and preserve, where possible the integrity of the study (e.g. the patient is on placebo) but allow for full scientific review of risks and actions to take.
Other Clinical Trials and Studies
Similar issues as seen in phase I but with some marked differences:
- These studies are often out-patient studies performed at many clinical sites of varying skill on several continents in large numbers of patients. But the same requirements apply: There must be a mechanism for immediate, receipt and evaluation of serious and severe safety issues. With more patients who are often quite ill, SAEs will be frequent; in long trials there will often be SAEs in a majority of the patients. They need to be evaluated and acted upon rapidly or even immediately. A 365 day, 24/7 mechanism must be in place.
- The operational issues here can be daunting covering many time zones, several languages, different medical quality levels and practices, difficulty in evaluating expected.
- All study documents should be accurate, medically correct and up to date. This includes the protocol, the Investigator Brochure and the Informed Consent. The appropriate surveillance groups (Health Agencies, DMCs, SACs, IRBs etc.) must be notified rapidly as both required by law and as appropriate medically and ethically.
The Post-Marketing Situation
Terrible safety issues can occur at any time during the marketing of a drug. Sometimes the issues are related to the drug itself but there may be other issues not due to the drug or active moiety such as counterfeiting, tampering, medical errors etc.
- This can be, in many respects, more difficult than the clinical trial situations since much is out of control of the company. The drug safety group may not be able to get full or correct medical information about the case. Secrecy and data privacy rules may limit access to the data. Far away time zones, language, limited access to the medical personnel treating the subjects or patients, social media, attorneys etc. may make getting information difficult or impossible. Nonetheless, even with incomplete information, the company must act in the best interests of the patients, subjects and public health.
- The operational aspects of this can be difficult if the drug is sold in multiple countries, if there are business partners also marketing and/or studying the drug, viral information spreading on social media etc. Nonetheless, solid procedures to discover, evaluate and minimize risk and harm must be in place.
What Should Sponsors, IND/NDA/MA Holders Do?
There should be no surprises here:
- Be sure the appropriate personnel, SOPs, communications mechanisms and all the other aspects of clinical trials and marketing of drugs are in place and up to date.
- Be sure that a crisis management SOP and mechanism is in place that can be called into action within minutes to an hour or two at most. Don’t forget the lower level support personnel in drug safety, regulatory, clinical research etc.
- Be sure someone is in charge at the senior level who is empowered to make major decisions. Although there may be a senior safety committee comprising medical, clinical, regulatory, legal, quality, manufacturing, toxicology etc., somebody must have the authority to make the critical decisions about recalls, stopping studies etc.
- Be sure the appropriate lists of people and contact information are available for any actions that need to be taken: all the countries where the drug is sold or studied, investigators, wholesalers, business partners, regulators, consultants, lawyers, IT, social media personnel (webmasters) etc. This list must be available 24/7.
- Spokespersons must be designated for media contact, the internet etc.
- Usually early contact with the regulators is wise. There should be a mechanism to discuss this at the highest level in the company. All regulators should be informed simultaneously. Say the same thing to everyone.
- Track and document in writing all discussions and actions. Understand that if litigation occurs, you may have limited access to documents including your own.
- Decide who needs to know what and when.
- Be ready for an inspection by one or more governmental agencies.
- Small companies working with a CRO or multiple CROs must be ready and able to manage the situation. Remember the ultimate responsibility lies with the sponsor not the CRO.
- Always do the right thing medically, legally and ethically.