Bart’s Corner: Escalating Signals and Safety Issues

Sep 10, 2014
Bart Cobert

医薬品安全監視、医薬品安全性および規制関連業務に関する執筆者・専門家

In modern day pharmacovigilance (PV) and Drug Safety (DS), whether it is done in companies or health authorities, it is absolutely necessary to have in place a mechanism both to identify safety issues and then to act on them.

There has been much discussion about the identification of safety issues and “signaling”. This is now a very visible function in DS and PV and mechanisms are in place in almost all companies and authorities to find pharmaceutical safety issues. Many companies then have mechanisms in place to further investigate and characterize the newly found issue. Some companies do not and out-source the work up to a third party or business partner. Although there are no clearly agreed upon categories of safety issues (possible signals, strong signals, potential signals, weak signals etc.) most organizations have a rational and defensible system of categorization and follow up for safety issues.

What is less clear in companies and health agencies is how to escalate the signal within the institution to get the appropriate actions taken. These include, primarily, protecting the public health but also protecting the company, complying with regulations (not just FDA but sometimes SEC and other obligations that public companies have to inform shareholders and the public), protecting the product, minimizing lawsuits and other adverse market effects. Although one may wish that the duties of safety should be to “protect the public, period!” the reality is that all of these other issues come into play: politics, regulations, marketing, sales, lawsuits, etc.

Thus the tricky part of a signal may not be the science and medicine of the signal and its work-up but rather proposing one or several courses of action to resolve the issue and then getting the appropriate people to “buy in” and put the actions in place. This is particularly difficult if the issue is a crisis or highly urgent with actions required immediately.

The DS and PV groups that handle safety for companies, CROs, health agencies etc. should do several things to be sure that their institution can handle this:

Organization

  • Is the organizational structure clear and precise?
  • Is there a DS/PV group or another group handling signals?
  • Is there the appropriate hierarchy of responsibility within this group?
  • Is there a physician in the group who can make a medical judgment? If a physician does not do it, does that person have immediate access to a physician?
  • Is there an up-to-date organizational chart (organogram)? Does it have names in addition to titles?

Signaling

  • Is there a signaling system with assigned responsibility and someone with authority overseeing it?
  • Is there an SOP (or other procedural documents) covering signaling?
  • Is signaling done and evaluated in a group or by individuals?
  • Are there periodic meetings to review signals with written minutes?
  • Is there a signaling list with dates, responsibilities, assigned tasks, prioritization?
  • Is there a mechanism to raise a safety issue to the next level up or to the client (if a CRO) etc?

Every institution handling DS/PV must have these in place in some form or another. It is not sufficient just to collect, process and report ICSRs, SUSARs, SAEs, SARs etc. In addition, they must be reviewed individually and in aggregate in the context of the known benefit-risk status. That is, someone or a team must analyze the reports in an on-going basis to see if new signals are developing or if old, known SAEs or NSAEs are changing in severity, frequency, quality etc.

The “Junior Safety Committee”

The next stage in this process can vary from company to company or institution to institution. Some will have a “junior” level committee to evaluate the safety issues along with a Senior Safety Committee. Other companies, particularly small companies, will combine these two functions into a single committee.

The junior committee may be called many things such as the Safety Committee, Signaling Committee, Risk Evaluation Committee etc. By “junior” what I mean is that its function is to evaluate the safety issue, perhaps ask for a further work up, literature review, evaluation by an internal or external consultant, reanalysis of the old, known cases in the database etc. Its function is to gather as much scientific information as possible to make a rational judgment on the next steps. The word “junior” is never used in the title but the clear understanding is that they collect data but do not make the decision on further actions. They may, depending upon their SOP, make recommendations to the senior committee or may simply present the data and facts and let the senior committee decide on the possible courses of action and make the final decisions. The key point here is for the junior committee to clearly understand its role and not restrict or box in the senior committee. That is, the junior committee should leave the senior management committee with all possible options.

  • Does such a committee exist and is there an SOP describing its function?
  • Are there regular meetings and are written minutes kept?
  • Who is the chairperson and what level of empowerment does he/she have?
  • Is there the possibility to call emergency, ad hoc meetings to respond to safety crises?
  • Is there a clear mechanism to escalate safety issues to the senior level on both a routine and emergency basis? Is it done in writing, orally/phone or both? Who will do this?
  • Is the committee purely scientific/medical? That is, there should not, as a rule, be marketing or sales personnel on the committee.

The Senior Safety Committee

As noted, some companies will have a single committee that will handle both the work-up of safety issues and the decision on what further steps to take. Other companies will have a formal Senior Safety Committee. Again, this may be called by various names such as: Clinical/Pre-Clinical Safety Surveillance Committee etc., the Safety Committee, the Labeling Committee (A bit of a misnomer but I’ve seen labeling committees have this responsibility. It doesn’t matter what the committee is called as long as this function is present and clearly defined in writing).

The mission of this committee is to make the final decision on the safety issue. The committee must be empowered and speak for the corporation, agency etc. Minutes must be kept. The minutes should describe the issue and the action steps but avoid a “he said/she said” description of the meeting. The members are usually senior corporate personnel such as the Head of DS/PV, Head of Regulatory, a Legal Department representative (a lawyer), Head of Medical (Research), Quality/Compliance, Corporate Risk Management and others as needed on an ad hoc basis (e.g. toxicology, manufacturing). In general Marketing and Sales should not be present but, in fact, they often are. If they do attend, they should not be voting members as a rule. The point here is that the committee must act in the best interests of the public health. The effect on sales or the stock price or other such non-medical matters should not come into play. The reality is, though, that these non-medical areas do come into play. However, the chairperson and senior management must ensure that all decisions are made to protect the public health with corporate matters secondary. The minutes should reflect this.

The committee may request any or many actions including: continue to observe/work up and report back to the committee in x days/weeks, stop or modify a study, withdraw a lot or drug from the market, emergency changes to the product labeling or Investigator Brochure (in all or some markets), notify the FDA, EMA etc. This can become very complex if there are multiple research or marketing partners (who have a say in the decision) or a drug with different indications in different countries or approved in one country but only in clinical trials in another etc.

The committee must have a global view and determine whether actions must be taken abroad not just locally. The obligations of business partners, co-marketers/co-developers, CROs and other third parties must be taken into account.

Clear assignments by name and due date must be made and these actions must be conveyed to the appropriate personnel if they are not present at the meeting. In a large company or regulatory agency, this can be a massive undertaking. Anyone who has ever dealt with a drug recall down to the pharmacy level in 100 plus countries or stopping a study with 500 sites or notifying hundreds of health agencies, IRBs, investigators etc. realizes what a large and complex situation this is.

Usually in such situations, a project manager is brought in from somewhere in the company to coordinate this. If the media must be alerted (e.g. a recall) this too must be handled. As noted, ownership and responsibility must be crystal clear. Nothing must fall through the cracks.

In some companies, this committee may need to get approval for all major actions from the CEO. This can be particularly tricky if the CEO is a micro-manager and wants to have a hand in all matters. There must be a system in place to ensure that he/she is available to make decisions.

Bottom Line

The escalation function for safety matters, particularly serious safety issues, must be in place and functional at a moment’s notice. This function will be high on the list of an FDA or EMA inspection. Failure to act rapidly and appropriately, particularly if the safety issue is first picked up by a health agency, can easily turn into a nightmare scenario.

 

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