22. Case Follow-up

The information from adverse event cases when first received will generally be incomplete especially for spontaneous reports and line listing published articles.   It is really critical to perform follow up to obtain missing information as well documented serious expected cases are potentially of epidemological interest in helping to identify risk factors and non-serious unexpected cases are also of potential interest for detecting a new signal. 

Although procedures are already in place within companies and regulatory authorities, guidance is needed to ensure that resources for case follow-up are focussed on the most relevant data elements for the most important cases for both marketed and investigational drugs. While performing follow up below factors need to be considered: 

1. Source of the report: literature, newspaper or other media, consumers, pharmacists, physicians, dentists, other healthcare professionals, company representatives, or from the patient’s lawyers. (If there is a case with legal implications, it is advisable to involve the legal department.) 

2. The most appropriate or effective method (site visit, letter, fax, e-mail, telephone) and how many attempts should be made 

3. For consumer reports, the need for medical confirmation in some countries adds another dimension to the process

4. The methods available for follow-up may be driven by the local authorities. 

5. The ‘‘age’’ of the drug: is there a possibility of diminishing returns on investing efforts on well established products. But other factors probably outweigh such considerations (e.g., serious unexpected cases and new drug interactions) 

What specific follow-up information should be sought? 

The ICH E2B guideline for individual safety case reports contains an extensive list of data elements. However, it is not expected that all such information would be available for most cases; indeed, it would be rare. Any missing information should thereby be sought through follow-up efforts.

Sometimes we might receive the information that are not on the list, this information also should be recorded and reported as appropriate; however, follow-up is recommended only when the data elements on the Lists are missing or incomplete. 

The CIOMS Working Group has developed the lists of data elements are referred to as Lists A, B and C for specific follow-up information to be sought for the various types of cases. 

For non-serious, expected cases: no follow-up recommended if all of the following are available (List A): 

• country of occurrence
• an identifiable reporter
• an identifiable patient
• source type (e.g., physician, lawyer, regulatory authority, etc.) o a suspect drug or drugs
• one or more adverse event. 

For serious expected and non-serious unexpected cases: In addition to the items in List A, the following should be available (List B): 

• Daily dose of suspected medicinal product and regimen 
• Route of administration 
• Indication(s) for which suspect medicinal product was prescribed 
• Starting date (and if relevant, time of day of treatment; e.g., acute hypersensitivity reaction) 
• If serious, criterion or criteria for regarding the case as serious o Full description or reaction(s) including body site and severity o Starting date of onset of reaction (or time to onset)
• If not available, best available date or treatment duration 
• Time lag if ADR occurred after cessation of treatment
• Patient outcome (at case level and, when possible, at event level): 
• Information on recovery and any sequalae. 
• Dechallenge information (if any) 
• Rechallenge information (if any) 
• For a fatal outcome, cause of death and a comment on its possible relationship to the suspected reaction(s) 
• Causal relationship assessment 
• Other relevant etiological factors

For serious unexpected, and ‘‘special interest’’ cases: everything in Lists A and B plus the following (List C) also required: 

• Stop date and time or duration of treatment  
• For concomitant medications:
• 1. Daily dose and regimen
• 2. Stop date and time or duration of treatment 
• Specific tests and or/treatment required and their results 
• Setting (e.g., hospital, outpatient clinic, home, nursing home) 
• Any autopsy or other post-mortem findings 
• Whether or not the hospital discharge summary is available if the patient was hospitalized. 
• Anything relevant to facilitate assessment of the case such as medical history, relevant drug history including allergies, drug or alcohol abuse, family history. 

Good Follow-up Practices:

• When laboratory or other tests are conducted specifically to investigate the case, results should be obtained for all such tests. Specific investigative tests should be the focus and must not be confused with routine tests conducted independently of the adverse event. 
• Medical confirmation should be sought from a medically qualified healthcare professional involved in the patient’s care if the report originates from other than a physician if the case is serious or medically significant. 
• Regulators are expected to share cases they receive directly with the relevant manufacturer(s), especially serious, unexpected reports; therefore, any follow-up obtained by the regulators should also be transmitted to the manufacturer(s). 
• Every effort should be made to follow-up unexpected deaths or life- threatening events within 24 hours of ascertainment by a company that such a case exists. 
• Follow-up information should be obtained in writing, via a telephone call, and/or a site visit as appropriate. Written confirmation of details supplied verbally should be obtained whenever possible. 
• If it is not possible to obtain full details by telephone or through a site visit, follow-up information should be requested in writing (for example, by supplying a partially completed regulatory or company form that includes a draft narrative, when appropriate, with a cover letter identifying the additional key information sought). 
• Acknowledgement letters should be sent to providers of follow-up information which should include relevant feedback, whenever possible (e.g., a planned labeling change). 
• Collaborative follow-up may be necessary if more than one company’s drugs are involved. 
• If the first written follow-up attempt on a serious unexpected case or a non-serious unexpected case fails to generate a satisfactory response, a second follow-up letter should be sent no later than four weeks after the first letter. In general, when the reporter does not respond or is incompletely cooperative, the two follow-up letters should reflect sufficient diligence. 
• For non-serious expected cases requiring follow-up (List A), only one letter (or equivalent communication) should suffice. However, for cases falling under Lists B and C, two letters or other communication should be the rule; for List C cases, a site visit may be needed or advisable. 

How long follow up need to be performed?

There are no guidelines on how long a company should continue to obtain information on the clinical course of an ADR and on what constitutes a reasonable effort. Because each clinical situation will be unique and require judgment, more specific guidance on how long to follow-up is not appropriate.

Consideration should be given to informing regulators, particularly on important cases, if all attempts to obtain follow-up information have failed. This allows them to ‘‘close out’’ the case within their files.