Different Regulatory Actions from Different Agencies

In late May 2019 the EMA rejected a drug for approval that the FDA had approved two years earlier.

In July 2017 the FDA approved Endari (L-glutamine oral powder) for the treatment of sickle cell disease noting it was the first new treatment for this devastating disease in 20 years. FDA noted that Patients who were treated with Endari had fewer hospital visits for pain on average, compared to patients who received a placebo and fewer days in the hospital. Patients who received Endari also had fewer occurrences of acute chest syndrome compared with patients who received a placebo.[1]

The EMA’s CHMP however refused approval of the application for Xyndari (glutamine) from Emmaus saying: “The CHMP considered that the main study did not show that Xyndari was effective at reducing the number of sickle cell crises or hospital visits. A large number of patients, more who were taking Xyndari than taking placebo, dropped out of the study before it was finished, and information on how the medicine worked for those patients was not available. The CHMP considered that the way data from these patients were dealt with was not appropriate.” [2]

These are exactly opposing conclusions as the FDA considered the data acceptable and sufficient for approval and marketing and the EMA did not. The clinical study data submitted appear to be the same for both agencies though the post-marketing data would be different due to two years of marketing experience.

Similarly, in May 2019 Radicava (edaravone), from Mitsubishi/Tanabe for ALS was not approved with the EMA calling for an additional survival study. [3] The drug was approved by the FDA in 2017 for marketing. [4] Several other countries have also approved the drug.

Sometimes the situation is much more straightforward. The exact same PSUR, signal document or various other aggregate reports as well as an expedited report may be submitted to multiple agencies at the same time. Thus each agency is seeing exactly the same information. They may still reach different conclusions.

There are many potential reasons for these differing opinions and communications. To understand the impact on pharmacovigilance and drug safety several things must be considered.

Was the disparity in the differing reactions of the agencies based on:

• Clinical trial data only.
  • Were the data identical? If the submission is months to years later there may be additional data, extension data, reanalyses etc. from the key studies. Was there new clinical trials done since the initial agency reaction?

• Post-marketing data only.
  • Those in the field of PV and drug safety know very well that post-marketing data, with all its inherent limitations, may still add significant and credible information that is quite different from the more narrow and rigorously done clinical trials.The new data may come from further trials, observations, epidemiology, patient support programs etc.  It may come from the literature, other health agencies, poison control centers, social media, lawsuits etc.

• A combination of clinical trial and post-marketing data.
  • This can be straightforward sometimes.  The post-approval data may reveal new efficacy uses, limitations or contraindications, vulnerable patient reactions, overdose information, concomitant medication interactions and more.  The post-marketing data may also confirm a possible signal known at the time of approval.  Or, indeed, it might refute the signal.

• Do the agency disparities concern efficacy or safety or both?
  • Efficacy – The data may be interpreted differently by the various agencies as in the first example. The FDA noted that the data showed fewer hospital visits for pain and fewer days in the hospital and fewer occurrences of acute chest syndrome.  The EMA, on the other hand, felt the data did not show fewer hospital visits or sickle cell crises.  The EMA also felt the dropouts, larger on the drug than the control, had insufficient data on drug efficacy till time of dropout.  Thus, the agencies interpret the data and their quality in different ways and then come to different conclusions on approvability.If the issues relate to lack of efficacy, the issues may not evolve rapidly nor require emergency responses unless the patients are critically ill, represent a vulnerable patient population or present a public health emergency (e.g. counterfeit drugs etc.)
  • Safety – Issues that involve urgent safety matters may indeed elicit urgent responses by different agencies especially if they feel patients are at risk for serious or severe consequences. Sometimes if the SAE/SAR (s) occurred in one country, the agency for that country may react more strongly than agencies far away.  This may be less so now with viral social media transmissions.

Comments & Lessons Drawn

Timing issues

The author remembers an episode some years ago when the same expedited report on a newly approved drug was sent to the FDA and several agencies in the EU. Unfortunately, for administrative reasons, the FDA report was submitted on day 8 and the EU report on day 14. Both were exactly the same. The FDA contacted us rapidly to discuss the situation and requested further follow up and heightened surveillance for the SAE/SAR that was reported. The EU agency was furious that they received the report 6 days later than the FDA even though it was not submitted late (not more than 15 calendar days). Evidently the two agencies talked to each other. The company’s senior safety and medical officers were summoned to Europe from the US and scolded. The agency came very close to requesting the immediate market withdrawal of the drug in Europe. After much discussion the agency was placated and did not require market withdrawal but did require additional clinical trial work. The lessons drawn were:

• Say the same thing to all health agencies at the same time. If this is not feasible, explain why with full transparency.

• Expect new and serious safety issues to elicit strong and rapid reactions in some cases. In some cases the responses will be different or even contradictory. Sometimes the reasoning behind the decisions will not be explained, will not be clear and may not even make sense to the reader. Sometimes the agency knows other details about similar drugs or occurrences but is constrained from revealing it. If a response appears irrational there may indeed be other factors that you are unaware of which make the response quite reasonable and rational in the eyes of the agency.

• Rational responses to all agencies must be made. Contradictions from other agencies may indeed be pointed out. If different things are said or promised to different agencies this should be communicated to all the agencies.

Communication

The agencies talk to each other. Companies should not try to play one agency off against another. This will lead to disaster. Companies and agencies should engage their internal (and if needed external) communication experts to clarify what should be said when to all stakeholders. Senior management should be involved if the issue is controversial and significant.

Minimizing

Do not try to immediately exonerate the drug unless the evidence is crystal clear. More likely, if there are two different opinions from different agencies, the issue is arguable. Causality may be unclear. The company should not try to minimize the situation. The submission should not be “written by marketing”. That is, particularly for safety submissions, the information submitted should be factual, non-emotional and scientific. One should not presume the drug is innocent until proven guilty beyond reasonable doubt. Some agencies will view the drug or situation as guilty till proven innocent.

One voice

Both the companies and agencies should each speak with one voice. There should not be multiple opinions offered, either on the record or off the record, making contradictory statements. Anything said to the press or put on social media should always be assumed to be “on the record”. If there are people who feel aggrieved, whether in the agencies or companies, there may be leaks or whistle-blowing.

For serious disagreements, the agencies and companies should always react calmly and firmly indicating the full information is being sought (if not present), that the situation is being taken very seriously and the interests of patients and public health will be held paramount.

Legal and liability issues

As the US is often considered to be a somewhat more litiginous country than many others, it is possible that actions by foreign agencies will be picked up by the US legal community producing lawsuits and pressures on the US regulators to “protect the American public as well as the agency of XXXX protects its citizens”. Issues may get politicized also.

Social media

As noted above, some agency decisions may get rapid and visible coverage both in the classic media and on social media putting further pressures on the agencies and companies. Companies and agencies track this rather well nowadays. Issues can go viral in hours.

Bottom Line

Many of the conflicts between different health agencies’ comments are small. Many can be worked out in a calm and non-urgent manner. When such situations occur, take a deep breath, dedramatize the situation, obtain further information from the agencies where possible, apprise them of the contradictions in a gentle way indicating that you (the company) are, to some degree, caught in the middle. You may still end up doing conflicting and contradictory things against your desires but which are obligated by the agencies. If this is the case, this should be noted to the agencies and, where appropriate, to the medical community and other stakeholders. Each situation is different and must be customized.

Everyone must tread carefully and remember that the public health is paramount.

References:

[1] https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-sickle-cell-disease 

[2] https://www.ema.europa.eu/en/medicines/human/summaries-opinion/xyndari

[3] https://www.raps.org/news-and-articles/news-articles/2019/5/emas-chmp-offers-negative-opinion-for-sickle-cell

[4] https://pharmaphorum.com/news/fda/