Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition). William Gregory
This again may vary from country to country, but in general, if a case meets the four validity criteria, then it should be submitted even if it is not from a classic clinical trial. The FDA clarified this issue in its IND reporting guidance by saying that such cases must be reported. For large amounts of data (e.g., “data dumps” from poison control centers), the sponsor may wish to discuss with the agency how such large numbers of cases should be handled. The study protocol should specify how these data should be identified and handled and, in some instances, by agreement, will not be reported.
Q: I thought most of the reporting requirements for clinical trial SAE cases have been harmonized, so why does it seem so complex?
A: To a degree, there has been harmonization. Clinical trial deaths and life-threatening SAEs that are unlabeled and possibly related to the study drug are reportable in 7- and 15 calendar days, respectively. However, there are substantive differences between the way these reports are handled for the US FDA and the rest of the world. Outside the US, each individual SUSAR (suspected unexpected serious adverse reaction) should be expedited; causality is per either the investigator or the sponsor. While the regulatory definition of “serious” is consistent and there is a single, worldwide Investigator Brochure for expectedness, determination of causality for reporting to the US FDA is the responsibility of the sponsor (only). Further, the term “SUSAR” is not recognized in US regulation, even though the concept is the same. Across the globe there are many exceptions or other requirements, local language requirements if the case is a domestic case, non-expedited reporting if the case is not domestic, and so forth. Some countries want or require electronic reporting and others still take or require paper reports (e.g., CIOMS I or MedWatch forms). It is likely things will harmonize eventually, but they are not yet at the level of harmonization for post-marketing case reports. Note that there are different requirements for medical devices, combination products, and, in some countries, there are different requirements for over-the-counter products, neutraceuticals, biologics, and herbals. Finally, a drug may be in clinical trials and not yet approved for marketing in one country, and approved and marketed in another country with different reporting requirements.
Note that the United States spells “harmonization” with a “z” (pronounced “zee” in the United States and “zed” elsewhere) and the UK and others as “harmonization” with an “s”. So, we have not yet even harmonized spelling and pronunciation!
CHAPTER
3
Spontaneous Post-marketing Adverse Events
When a new product reaches the market, a wider population is exposed and spontaneous case reports play a pivotal and irreplaceable role in providing safety information.
Before a drug comes to market, it is studied in patients in clinical trials that aim to show the efficacy of the product for a particular selected disease in a highly selected sample of the population. The clinical trials may be large, covering up to 10,000 patients, or very small, covering dozens to hundreds * patients (e.g., for orphan drugs or rare diseases). The clinical trials also aim to define the safety profile of the drug, at least in this selected population with this selected disease.
These studies, which are (usually) carried out with rigorous and highly regulated methodology are statistically powered to demonstrate efficacy, but have significant limitations in defining the safety profile. They generally only find frequently occurring adverse events (AEs). For example, if in studying 10,000 patients not a single patient has a particular AE, such as a heart attack, we can be only 95% confident that the chance of having a heart attack based on the data from this trial is less than 1 in 3,333. If we raise the safety threshold to be 99% confident that a heart attack has an incidence of only 1 in 10,000 with this drug, we would need to have no heart attacks in 46,000 patients studied. In other words, studying even 5,000 or 10,000 patients does not give a warm enough or fuzzy enough feeling that the major or rare safety issues have been identified before the drug goes on the market for large-scale use.
This means that the uncommon AEs and even the fairly common AEs (e.g., an incidence of 1 in 500) will not be picked up until the drug is extensively used in the general population after marketing. When, say, a million people start using a new drug in the months after a product launch, a “rare” AE with a 1 in 10,000 incidence rate could be expected in about 100 patients. Should the AE in question be dramatic and rapidly discovered, such as torsades de pointes, aplastic anemia, or rhabdomyolysis (a severe skeletal muscle injury), there will be a torrent of recriminations about why this was not discovered earlier during the clinical testing. The correct response is that the testing of only 5,000 to 10,000 patients could not pick up such a rare event because this is the way the drug approval system is designed. This response is usually lost in the clamor. There are now attempts under way to get a better handle on the safety profile before marketing and to follow the safety (and benefit) profile after marketing in a much more rigorous manner.
Also of note is that the clinical trials are often done in a narrow group of patients. For example, an antihistamine may be tested in otherwise healthy adults between 18 and 60 years of age with allergies. Even if the drug is only approved for use in this population, physicians in most jurisdictions have the right (which they freely exercise) to prescribe the drug for anyone and for any disease. Thus, many people with other diseases and at the extremes of the age range (the very old and young) receive the drug and may have AEs that the healthy 18- to 60-year-old study population did not experience in the clinical trials. The elderly, for example, are particularly sensitive to certain AEs (e.g., swallowing disorders) or to certain classes of psychotropic drugs.
Polypharmacy and drug interactions, among other things, cannot be adequately studied in the preapproval setting. Although food interaction studies and some drug interaction studies are done before approval, it is not possible to study “real world” patients (often elderly) who take many drugs and have peculiar or irregular eating and drinking habits. Even after marketing, it is difficult or even impossible to predict or know how the use of three, four, or more drugs given at the same time will act or interact.
Hence, particular attention must be paid to the time just after a product is first marketed to fully understand the drug’s safety profile and minimize risks. In a sense, the first 500,000 to 1,000,000 patients who are prescribed the drug after launch are doing the large-scale safety testing. And, outside of clinical trials, the reporting of safety information by healthcare practitioners and other members of the public to manufacturers and drug regulators is nearly always voluntary.
What this means then is that the entire edifice of the drug safety system as it now stands, depends on the good will and energy of nurses, pharmacists, physicians, and consumers to report AEs. Without them, no one would know of the AEs that are appearing as individual cases in isolated areas around the country or the world. These people must take time out of their day to report such events. The report will inevitably lead to a request for supplementary data (laboratory reports, cardiograms, hospital records, etc.) that are time- and effort-consuming. There is no evident or immediate gain to the reporter. The gain rather is to society at large, which is largely unaware of this noble effort.
Health authorities and regulators well understand the weakness of this system. Major efforts are now under way to look at how the spontaneous reporting system has worked in the past. That is, although we think it is useful and appropriate to rely on this system, did it, in fact, lead to early pick-up of serious problems, leading to a change in the product labeling and its use in clinical practice?
Various health agencies, particularly in North America and Europe, are looking at this question.
There is a lot more digital data, sitting in the cloud, on drug safety that are not being looked at in a systematic manner. Obtaining these data on an ongoing basis and using them for safety analysis is an obvious way to identify a drug’s safety profile. However, the devil is in the details.