In my thirty years in this business doing both medical and operational drug safety and pharmacovigilance, I’ve seen that just about every possible permutation of handling expedited reports has been used.
In many cases, it does not matter how such reports are handled and most of the different methods work well. However, there are some issues that are critical and where auditors and inspectors will ding you.
The point of the 7 and 15 day expedited reports is that the health agencies want to see certain cases asap in a clear and scientific writeup. This is particularly so for products that are in phase I (where any SAE is to be examined very carefully especially if the subjects are normal volunteers), toxic products, products used in very ill patients and newly launched products.
Not all fields in a MedWatch, CIOMS I or E2B submission are equally important nor should the amount of time and energy expended be the same for all fields. Several of the critical fields are:
- Age and sex
- Comedications
- Concomitant illnesses and, perhaps to a lesser degree in some cases, medical history (not sure the appendectomy 35 years ago is that important…)
- The narrative
- MedDRA codes of SAEs and AEs
- Dosing and SAE onset date
- Reporter (medical professional or not) & documentation
- Relevant tests
Fields and determinations that are less looked at include:
Causality by the company and investigator for clinical trial reports
Why is this? FDA has addressed review of safety information in an NDA or BLA submission and its comments are applicable both there and in individual case reports. FDA has written:
“The analyses of drug-related AEs presented by applicants are usually based on assessments made by investigators at the time of an event (with sponsor responsibility), which are highly dependent on information about the safety profile of the drug available at the time of the study, e.g., what is in the investigator’s brochure, and are not informed by awareness of the entire safety database. These sponsor/investigator analyses are generally not expected to provide much useful information in the FDA assessment of causality.”
Are causality analyses ignored? Certainly not, but they are taken with a grain of salt particularly where the company says not related and the investigator says possibly related. Such analyses and determinations must be done and must be done with honesty and a view that the drug might indeed have caused the SAE unless there are clear reasons to state otherwise. See: Attachment B: Clinical Safety Review of an NDA or BLA
Certain demographic fields: height, weight
Detailed dosing schedules
Of course doses are important but in the world of DS/PV it is often less critical whether the patient took the drug for 3 weeks or 6 weeks. In evaluating compliance for efficacy analyses this does matter and lack of compliance may eliminate the patient from the efficacy analysis but never from the safety analysis.
Let’s look at the higher priority fields:
Age and Sex
Age can be a critical determining factor in evaluating a case. A medical problem in an elderly or high risk patient may be much less striking than in a healthier younger person. A myocardial infarction, for example, is certainly important to evaluate in a 65 year old with risk factors but would be strikingly more important in a 25 year old healthy person. A lower hematocrit in a menstruating female may be less important than in an elderly post-menopausal woman.Similarly, sex can suggest that this is a risk factor for an SAE. Again, looking at myocardial infarction, this is less common in pre-menopausal women and when it is seen in such a patient, this may be an important factor. Breast cancer in a man is very noteworthy.
Comedications
Obviously some medications may produce the SAE(s) in question and if the patient is on one or more medications that are possible confounders, this is important to know. In the world of polypharmacy (frequent in the older populations) this is a very important field. Diligent efforts should be made to obtain a complete list of comeds including OTCs.
Concomitant illnesses
Obviously also, other factors can play a role in case assessment including other illnesses. Patients in long-term studies may get the flu, have accidents, go to the dentist, have scheduled procedures etc. These should also be carefully sought and included; they many not always be remembered easily or volunteered.
The Narrative
This is the “heart” of the case. A good narrative should summarize the case in a few paragraphs so that the reader can have a good feel of the case before delving into more detail (e.g. in attached CRF pages or medical records). All too often now the narrative is hundreds to thousands of words long and includes dozens of lab tests (many are repetitive and convey no new or important information). The trend now is for data dumps and very “complete” narratives. This makes reading the case very painful. One understands the idea of wanting to be more complete than less complete but often this is carried to the extreme.In the worst cases, follow-up information is appended to the (long) initial information making the reader go through the entire initial section before coming to the follow up information which is often not clearly marked or indicated. Multiple follow-ups compound this situation even moreso.
Another area that makes the narrative difficult is when a patient has a long and complicated course following the initial SAE. For example, if a patient is admitted for a myocardial infarction, is diagnosed and treated and then has another problem (e.g. falls out of bed and breaks a hip) or catches pneumonia and has a long downhill course leading to shock, cardiopulmonary arrest and death, it is usually not very relevant to the evaluation of the SAE to spend much time describing the hip surgery or the treatment of cardiogenic shock listing all the medications given. These “cascade” events should be mentioned but the detail is probably not relevant. The medical reviewer or team should make the judgment of what is important and what can be covered briefly.
Ideally, a narrative should read like a hospital discharge summary in which a concise review of the important issues are noted and the extraneous matters or the issues that have been ruled out are mentioned only briefly or not at all. At some point in a long case, the narrative should be rewritten rather than new data appended. The rewrite should give the date of the initial information and then, each starting a new paragraph, give the date and detail of the follow up.
MedDRA Coding of SAEs and AEs
This is an area I have found very troubling. First there is the issue that many companies do not code well or consistently. MedDRA coding is an art and in many cases judgments have to be made about how to code. Sometimes a direct hit may not be a good code at the LLT or PT level if the SOC is inappropriate. This is where medical judgment is needed. Everyone should be trained in coding and up to date on the MSSO’s Points to Consider document.
Next is the question of “how many codes.” I’ve seen the gamut from one code to over a dozen in expedited reports. Sometimes only a single term is appropriate but often it is not. Similarly, a dozen may be far too many to evaluate whether a drug caused a particular SAE. I’ve seen some sponsors set an arbitrary limit of 5 or 6 codes at most and any more must be approved by someone higher up.
Coding the event that caused a fatal outcome may not always be appropriate or sufficient. I’ve seen a case where the only SAE code on the MedWatch was peritonitis. The narrative goes on to explain, however, that the patient actually had diverticulosis, developed out of control diabetes and took a concomitant drug that slowed GI motility. This produced a colonic perforation which was, unfortunately, not picked up for several days. When it finally was, the patient went to surgery and severe peritonitis was found. The case was not one of possible drug induced peritonitis but rather seemed to be one of perforation and a motility disorder. The peritonitis was secondary to lack of rapid diagnosis and treatment. The coding here should have included the diabetes, the perforation and perhaps also the diverticuli.
This raises the question of how “cascade” SAEs should be coded or whether they should be coded at all. In the case above, one could argue that a truer picture (in terms of the SAE’s relationship to the drug) would have been coding of the motility disorder and perforation rather than the secondary “downstream” SAE of peritonitis. This can be done either way but one should be consistent.
Some companies do not ever code non-serious AEs in an expedited report. To me this is a mistake and can be very misleading. In the case above, the out of control diabetes (as expressed by an elevated blood glucose) may have been an important factor if the drug also elevated the glucose. This should have been coded, particularly if the patient had been in good control or had no evidence of diabetes before starting the drug. If the out of control diabetes was only mildly so then this would be a coded non-serious AE. If severely out of control, then it should be a serious AE.
So the bottom line here is that medically important non-serious AEs should be coded too. Of course, they should be mentioned in the narrative.
Dosing and SAE Onset Dates
Obviously this is important in the evaluation of causality. Time to onset, Cmax, Tmax etc. may be very important. This information is critical.
Reporter and Documentation
Also important. If a case has medical “validation” that adds to the strength of the case. A patient reporting “shock” may not use the word in the same sense that a medical person would. Supportive documentation from the lab, hospital or office records are similarly important.
Relevant Tests
Often the whole series of lab tests are dumped into the narrative or other sections of the MedWatch or E2B report. If the tests are not in tabular form, it may be very hard to compare the hematocrit from week to week or see trends if one has to jump around in the narrative. The title of the field on the MedWatch/CIOMS contains the word “relevant” and this means some judgment should be used.
Finally, I’ve seen 10 page MedWatch forms usually with multiple follow-ups and very long narratives making reading impossible. As noted, when a case becomes long, the narrative should be rewritten in a manner to show the sequential arrival of the data without appending it (and repeating whole paragraphs).
Now that Quality Management Systems are in place, we are starting to see auditors and inspectors criticizing the quality of the expedited reports not just lateness or errors. It’s time to pay attention to this.
