In planning the clinical program for drug approval, in addition to the efficacy assessment, the adequate size of the safety database is usually required by the regulatory agencies. Unlike the efficacy assessment while the sample size can be calculated, the size of safety database is a little bit vague. The size of safety database is often included in the pre-IND meeting with FDA because the sponsor would like to understand the expectation from FDA regarding the size of safety database. There could be situations that the sample size for demonstrating the efficacy is relatively small and the overall clinical development (cost) would largely depend on the size of safety database.
The reference guidelines regarding the size of safety database are mainly the ICH E1 (The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-term Treatment of Non-Life-Threatening-Conditions) and FDA guidance “Premarketing Risk Assessment”. The guidance is pretty specific in terms of the size of safety database “For products intended for long-term treatment of non-life-threatening conditions, (e.g., continuous treatment for 6 months or more or recurrent intermittent treatment where cumulative treatment equals or exceeds 6 months)
the ICH and FDA have generally recommended that 1500 subjects be exposed to the investigational product (with 300 to 600 exposed for 6 months, and 100 exposed for 1 year). For those products characterized as chronic use products in the ICH guidance E1A, FDA recommends that the 1500 subjects include only those who have been exposed to the product in multiple dose studies, because many adverse events of concern (e.g., hepatotoxicity, hematologic events) do not appear with single doses or very short-term exposure. Also, the 300 to 600 subjects exposed for 6 months and 100 subjects exposed for 1 year should have been exposed to relevant doses (i.e., doses generally in the therapeutic range)
In product label, the corresponding sample database description is provided in FDA guidance “Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format”
The data described below reflect exposure to drug X in [n] patients, including [n] exposed for 6 months and [n] exposed forgreater than one year. Drug X was studied primarily in placeboand active-controlled trials (n = __, and n = ___, respectively), and in long-term follow up studies. The population was [age range], [gender distribution], [race distribution] and had [diseases/conditions]. Most patients received doses [describerange, route of administration, frequency, duration, as appropriate].
However, for products intended for short-term or acute use and for products intended to treat life-threatening diseases, the guidance did not provide the specific requirement. The requirement of the size of safety database is usually based on the discussion with the review devision of the regulaory agency. FDA guidance “Premarketing Risk Assessment” did provide some general guidelines:
“Safety databases for products intended to treat life-threatening diseases, especially in circumstances where there are no alternative satisfactory treatments, are usually smaller than for products intended to treat diseases that are neither life-threatening nor associated with major, irreversible morbidity. A larger safety database may be appropriate if a product’s preclinical assessment or human clinical pharmacology studies identify signals of risk that warrant additional clinical data to properly define the risk. The appropriate size of the preapproval safety database may warrant specific discussion with the relevant review division. For instance, 21 CFR 312.82(b) (subpart E) provides that for drugs intended to treat life-threatening and seriously debilitating illnesses, end-of-phase 1 meetings can be used to agree on the design of phase 2 trials “with the goal that such testing will be adequate to provide sufficient data on the drug’s safety and effectiveness to support a decision on its approvability for marketing.”
“For products intended for short-term or acute use ( e.g., treatments that continue for, or are cumulatively administered for, less than 6 months), FDA believes it is difficult to offer general guidance on the appropriate target size of clinical safety databases. This is because of the wide range of indications and diseases (e.g., acute strokes to mild headaches) that may be targeted by such therapies. Sponsors are therefore encouraged to discuss with the relevant review division the appropriate size of the safety database for such products. Because products intended for lifethreatening and severely debilitating diseases are often approved with relatively small safety databases, relatively greater uncertainty remains regarding their adverse effects. Similarly, when products offer a unique, clinically important benefit to a population or patient group, less certainty in characterizing risk prior to approval may be acceptable.”
It is no surprise if FDA provides the following guidance to the sponsor “FDA has generally accepted a minimum of 300-400 subjects as the safety database to support an indication in the intended use population(s) to rule out with 95% confidence an adverse event that occurs with a frequency of 1%. “
Apparently, the above statement requires statistical calculation (or beyond the statistical calculation). If we use the SAS Proc Freq, we can actually see how the number 300-400 is played out.
input scenario Event $ count;
1 AE 1
1 no 294
2 AE 1
2 no 299
3 AE 1
3 no 554
4 AE 1
4 no 559
proc freq data=samplesize;
tables Event / binomial (p=0.01) alpha=0.05 cl;
**p=0.01 option indicates the standard rate to compare with,
here we assume the AE rate of 1%;
** Alpha=0.05 to obtain two side 95% confidence interval;
exact binomial; *Obtain the exact p-value;
The scenarios 1 and 2 are based on the calculation of the asymptotic CI:
For N=295 and event=1, the 95% CI =(0.0000, 0.0100), which meant with 295 subject safety database, it would not be able to rule out an AE that occurs with a frequency of 1%;
For N=300, and event=1, the 95%CI=(0.0000, 0.0099), which meant with 300 subject safety database, it would be able to rule out an AE that occurs with a frequency of 1%
The scenarios 3 and 4 are based on the calculation of the exact CI:
For N=555 and event=1, the 95% CI =(0.0000, 0.0100), which meant with 555 subject safety database, it would not be able to rule out an AE that occurs with a frequency of 1%;
For N=560, and event=1, the 95%CI=(0.0000, 0.0099), which meant with 560 subject safety database, it would be able to rule out an AE that occurs with a frequency of 1%
Even though the exact confidence interval is more appropriate when dealing with such low frequency of AE. It may be inpractical to impose a safety database of 560 subjects treated with the testing product.
The size of safety database may depend on the specific area in development. For example, FDA has its requirement for safety database on vaccine product. Below is the specific requirement from FDA guidance “Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines”
“Safety data must be collected from subjects enrolled in pre-licensure clinical trials intended to support the accelerated approval of a new seasonal inactivated influenza vaccine (21 CFR 312.23, 312.32, 312.56, 312.60 and 312.62). The monitoring of these subjects should follow the outline for safety evaluations described in Section III.A.3. above. A total safety database large enough to rule out a serious adverse event that occurs at a rate of 1 in 300 may be sufficient when a sponsor has adequate marketing and safety experience with the same manufacturing process for a seasonal vaccine licensed outside the United States and these data are presented in the BLA and assessed as such. For example, the upper limit of the two-sided 95% CI of the true serious adverse event rate is 0.0032 ( less than 1 in 300) when no serious adverse event is observed among 1150 subjects who received vaccine in clinical trials, using the Clopper-Pearson method. However, the size of the pre-licensure safety database, especially for seasonal influenza vaccines manufactured using novel processes such as cell-culture and for seasonal influenza vaccines that contain novel adjuvants, would be influenced by factors such as the nature of the new manufacturing process and available pre-clinical and clinical data, and should be discussed with CBER.Moreover, if a serious adverse event is present in a safety database of about 1,000 subjects, and there is concern that it may be vaccine-related, additional safety data may be needed. Safety data to support use in pediatric populations would also be needed and should be submitted either as part of the BLA, or as a clinical efficacy supplement at a later time, if pediatric studies are deferred under PREA (see Section III.C.4. - Pediatric Research Equity Act).”
Safety Database versus Safety Population
These two terms can sometimes cause confusion. Safety Database includes only the subjects who exposed to the testing drug and not control. Safety database is usually used for discussion of the entire clinical program (multiple studies). Safety Population is the term used in clinical protocol or statistical analysis plan pertinent to a specific protocol. Safety population defined as the subjects who received any dose of the study medication (includes both testing drug and control).