Читать книгу Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition) - William Gregory - Страница 35

Q: Does the company have to collect all AEs from all trials?

A: Basically yes, in one form or another, but there are exceptions. First, it is good medicine to collect all serious and non-serious AEs so that the sponsor has a basis to fully understand the safety profile of the product. Second, it is legally required in most instances. In practice, only SAEs must be collected from clinical trials in real time by the sponsor, i.e., the sponsor’s drug safety group. The data must be evaluated and reported to the authorities either in 7 or 15 calendar days or periodically in annual reports. Non-serious AEs and some SAEs (e.g., expected SAEs that the sponsor and health authority agree will be reported only at the end of the study) do not get reported until the final study report.

What this means is that in many pharmaceutical companies, two databases contain safety information. There is the drug safety database maintained by the drug safety group for expedited and periodic regulatory reporting and the clinical research database for marketing authorization and NDA submissions. The safety database contains all SAEs (as well as all serious and non-serious post-marketing AEs) but not non-serious clinical trial AEs. This database is dynamic and always up to date. The clinical research database contains the (paper or electronic) case report form information, including all serious and non-serious AEs.

Sometimes data are not entered into the clinical research database rapidly but rather only when paper case report forms arrive in the research department, perhaps monthly. In other cases, where electronic data capture is used instead of paper CRFs, the data entry at the site may be delayed or incomplete. Some companies using electronic data capture (EDC) also require an e-mail, fax, or direct download of EDC data into the safety department’s database. Nonetheless, the use of electronic case records should make data available more rapidly than in paper-based studies.

Having two databases produces various problems. To get a full picture of the safety in the trial, one must obtain the SAEs from the safety group (their database is usually up to date) and the non-serious AEs from the clinical research group’s database (which may not be up to date). The data outputs must then be reconciled (a problem if the two database outputs are not compatible or normalized) to have a full dataset. In addition, the SAEs in the two safety databases must be reconciled if the same SAE safety data are collected in two different places or in two different ways (e.g., EDC and e-mail/fax of the case to the sponsor’s drug safety group).

Signaling investigations should be done using all serious and non-serious clinical trial data no matter where they are stored or how they are obtained. This may mean the creation of a “data warehouse” to allow access to the data contained in both databases. It is likely that, as EDC and health data standardization advance, clinical trial safety data will be collected in one place without the need for double collecting systems.

Modernizing clinical trial data collection will have many implications:

Safety data (serious and non-serious AEs) would be received in real time.

Electronic data entry would be done remotely at each study site rather than centrally at the company or CRO. This takes the data entry out of the direct control of the company or CRO and put into the hands of employees (of variable skill levels and oversight) at each investigational site. Issues with training, personnel turnover, and quality maintenance at each site now become critical.

The company drug safety database may not be linked electronically to the EDC database, and new procedures would have to be developed to get the safety data to the safety group for entry into the safety database in an accurate and timely manner.

Source documents (e.g., laboratory tests, X-ray reports) might not be sent to the company now that studies are “paperless”. In fact, source documents may now be electronic, because the classic case report form no longer exists. Where paper source documents exist, they may need to be scanned and added to the EDC, clinical trial, or safety databases.

Getting follow-up information, which continues to be a challenge, will still remain difficult. One can envisage the day when the US, the EU, and other medical systems are standardized and online. All data, including study data and safety data, will be sent electronically in real time and simultaneously to all needed databases at the company, the health agencies, the hospital, the insurance companies, and so on. Safety data will be accurate and rapidly received everywhere they are needed. Maybe.

Q: Are phase IV study SAEs reportable as clinical trial AEs (to the IND in the US) or as post-marketing AEs (to the NDA in the US), or as both?

A: If a study is done under an IND or a similar pre-marketing situation, then the SAEs that meet reporting criteria are reported to the IND. Note that FDA would like only “informative” reports. Further, FDA is skeptical that causality can be attributed using reports of a single subject. Thus, similar reports in the aggregate are perceived to have greater value than single cases, particularly when background rates of the event are considered. Many companies believe that the NDA/MA takes precedence over the IND and would report those SAEs to the NDA/MA, also. This may vary from country to country, so local rules and regulations must be checked. SAEs from studies not done under an IND should be reported to the NDA and in most jurisdictions treated as post-marketing AEs.

Table 1. Summary of the US Safety Reporting Requirements for CDER-Regulated Products (from FDA Guidance, September 2010).

Note: *If a drug is approved in the United States, but is not currently being marketed in the United States, the postmarket requirements would still apply.

Q: If multiple companies or investigators are involved in a trial (whether it is an IIR or a formal company sponsored trial), should there be double (or even triple) reporting just to be sure the cases are not missed?

A: There is no logical reason for duplicate reporting in general and most regulators discourage this. If more than one company is involved, the protocol or other formal written document should contain an agreed-upon mechanism for a single company to handle safety reporting. In such situations, both companies may keep the AEs in their respective databases, but only one company should submit the cases to the regulatory authorities both as expedited and aggregate (annual) reports (and the companies should audit each other for compliance with the agreement).

In some situations, however, companies request that the investigator involved in IIR send a copy of each SAE ICSR to the company. The investigator, as the sponsor, must report such cases to the regulatory authority. The company, in many cases, will also report the case to the regulatory authority “just to be sure”, noting in the transmission that this is an IIR and that the investigator is the sponsor and should be submitting the case. Note that in certain cases a duplicate report must be sent to an IND and an NDA at FDA.

Q: Should AEs be reported from observational or epidemiologic trials or registries?

A: 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!