Sunday, June 23, 2013

Serious Adverse Event (SAE) Data Collection / Reporting Using Electronic Data Capture (EDC) System

Clinical trials require ongoing and continuous monitoring of the safety for study participants. According to 21 CFR 312.64, Investigators are required to “immediately report to the sponsor any serious adverse event (SAE), whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether or not there is a reasonable possibility that the drug caused the event.”

For industry sponsored clinical trials, investigators are typically required to report any SAE to sponsor with 24 to 48 hours of becoming aware of an SAE. The recipients of the SAE are typically the pharmacovigilence (PV) group or drug safety group who are independent of the clinical research team and are dedicated for receiving (from the investigational sites), clarification (with the investigational sites), analyzing, and reporting of SAE information. The transmittal of SAE from investigational sites to sponsor is typically through faxing or emailing the paper SAE form which is separated from the adverse event (AE) case report form used in clinical and data management group. Investigators will need to enter the duplicate information for SAE into the case report form (used by the clinical and data management group) and into SAE form (used by the PV or drug safety group).  Since the SAE information at clinical database and the drug safety database may have discrepancies, the SAE reconciliation is required to make sure the consistency between the clinical database and the drug safety database.

With more and more clinical trials conducted using electronic data capture (EDC) to collect the data, it is natural to think about the transition of SAE data collection for PV or drug safety group through EDC system instead of faxing and emailing the paper SAE forms.  By using EDC system to collect the SAE information, investigators will only need to enter the SAE data one time at one system (EDC). Once SAE information is entered into EDC, an alert will be sent to the designated group. This process will avoid the potential data discrepancies between clinical database and drug safety database and will avoid the necessity of the SAE reconciliation.  

One concern about this process is that SAE form typically collects more items than AE form. Additional information for SAE is required per ICH guidance E2B “MAINTENANCE OF THE ICH GUIDELINE ON CLINICAL SAFETY DATA MANAGEMENT : DATA ELEMENTS FOR TRANSMISSION OF INDIVIDUAL CASE SAFETY REPORTS

This concern can easily be addressed by adding these additional fields required for SAE reporting to the AE case report form in EDC database.  

CDISC/CDASH has just published an addendum to AE collection for serious events. The addendum specifically addressed the concern for collecting SAE through EDC system (instead of paper).

The page 4 of the CDASH SAE addendum says:

“Electronic data capture (EDC) is recognized as an efficient and time saving method for capturing clinical data. EDC also offers a more efficient process for SAE information capture than the traditional paper form; sponsors can use information already available in the Clinical Data Management System (CDMS) to populate the same data elements on an SAE report form. Typically, such data are housed in a clinical study database. All SAE data that are not extracted from the clinical study database are typically housed in a separate safety database. The relationship between drug safety data and clinical trial data that commonly manifests in two distinct data acquisition processes can be enhanced by minimizing duplicative data collection and easing the safety data reconciliation processes.

Clinical Data Acquisition Standards Harmonization (CDASH) is the standard applied to clinical data at point of capture (http://www.cdisc.org/cdash). CDASH contains an Adverse Event domain intended for capture of adverse event information in the CDMS (the AE CRF).

The draft CDASH Adverse Event Addendum to CDASH version 1.1 expands the current Adverse Event (AE) domain to include data elements for the capture of serious adverse event information in an SAE Form and, when indicated, will also allow for the generation of an E2B message for reporting an Individual Case Safety Report (ICSR) to Health Authorities. The content of an ICSR is specified by the International Conference on Harmonization (ICH) in the Guideline on Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports (E2B R2). “

Further Reading:

One-Sided Test in A Superiority Trial

In this year’s ATS meeting, the results for a studyZemaira in Subjects With Emphysema Due to Alpha1-Proteinase Inhibitor (API) Deficiency” (study acronym RAPID trial) was presented. The study was designed to test the superiority of Zemaira to Placebo in CT density endpoints. “According to study findings, the annual rate of lung density loss was significantly less in A1PI-treated patients (-1.45 +/- 0.24 units vs. -2.19 +/-0.25 units; p = 0.017, one sided).”  The interesting thing is that the one-sided test was used for testing differences between two treatment groups and one-sided  p-value was presented.   


The appropriateness of two- or one-sided tests has been the subject of controversy for over half a century. However, in clinical trials for regulatory approval, two-sided test is preferred and is almost uniformly adopted by the industry. ICH Guidance E9 “ STATISTICAL PRINCIPLES FOR CLINICAL TRIALS” clearly stated the followings:

“It is important to clarify whether one- or two-sided tests of statistical significance will be used, and in particular to justify prospectively the use of one-sided tests. If hypothesis tests are not considered appropriate, then the alternative process for arriving at statistical conclusions should be given. The issue of one-sided or two-sided approaches to inference is controversial and a diversity of views can be found in the statistical literature. The approach of setting type I errors for one-sided tests at half the conventional type I error used in two-sided tests is preferable in regulatory settings. This promotes consistency with the two-sided confidence intervals that are generally appropriate for estimating the possible size of the difference between two treatments.”

In RAPID trial mentioned above, the one-sided p-value was calculated as 0.017. This p-value would need to be compared with half of the conventionally significance level of 0.05. While p value of 0.017 is still statistically significant comparing to 0.025, people may wonder while two-sided p-value was not calculated for comparison to 0.05. In superiority trial, a p-value from one-sided test needs to be compared with 0.025 and a p-value from two-sided test needs to be compared with 0.05. Presenting the one-sided p-value may give a false impression that the study result is more significant since only smaller p-value is presented and the smaller (half) significance level is not presented. If the significant level is clearly stated and is presented along with the p-value, there will be no difference in understanding and interpretation of the results no matter whether one-sided or two-sided p-values are presented. If the one-sided p-value is 0.029, the result will not be statistically significant since the one-sided p-value needs to be compared to 0.025 instead of 0.05 even though it may give an wrong impression of a statistical significance.

Typically, clinical trials are designed as using two-sided test for primary efficacy endpoint. Randomized, controlled clinical trials are conducted due to the uncertainty of experimental treatment better than the comparator – equipoise. The statistical test must also consider the possibility (or probability) of experimental treatment is better than comparator or comparator is better than experimental treatment. This justifies the use of two-sided test.

If the benefit of experimental treatment is known to be better than the comparator - lack of equipoise, the one-sided test could be used, but the clinical trial would not be ethical to be conducted due to the lack of equipoise.

Sunday, June 16, 2013

Drug for Treating Rare Diseases: Orphan Drug, Orphan Disease, Orphan Subset

Section 526(a) of the Federal Food, Drug and Cosmetic Act (FD&C Act) defines a ‘‘rare disease or condition’’ as following:

any disease or condition which (A) affects less than 200,000 persons in the United States, or (B) affects more than 200,000 in the United States and for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from sales in the United States of such drug. Determinations under the preceding sentence with respect to any drug shall be made on the basis of the facts and circumstances as of the date the request for designation of the drug under this subsection is made.

In “Ophan drug act final rule” issued on June 12, 2013, Orphan Drug Regulations further clarified the term “ophan subject”
‘‘orphan subset’’ of persons with a particular disease or condition that otherwise affects 200,000 or more persons in the United States (‘‘non-rare disease or condition’’), for the purpose of designating a drug for use in that subset.

Regulations provided the incentives for sponsors to develop the drugs for orphan diseases. The incentives includes:
  • Seven-year marketing exclusivity to the first sponsor obtaining FDA approval of a designated drug
  • Tax credit equal to 50% of clinical investigation expenses
  • Exemption/Waiver of PDUFA application (filing) fees
  • Assistance in the drug development process
  • Orphan Products Grant funding


However, in order to obtain the approval, the clinical trials are still needed to demonstrate the efficacy and safety. The requirements specified in FDA guidance “Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products” will still be met.

A debatable question is whether or not there should be less requirement for orphan drug development studies:
  • Should one single pivotal study be sufficient for approval?
  • Should the surrogate endpoint or biomarkers be used?
  • Should there be different requirement for the size of so called ‘safety database’?
  • Should alternative clinical trial design or different statistical approaches be used? 
  • Should there be different drug approval pathways for orphan diseases? 


Given that the size of the patient population may vary in great deal depending on the type of orphan disease (orphan versus ultra orphan), it is not possible for the regulators to have an one set of rules that could apply to all orphan disease. The general desire from the sponsor side or patient advocate groups is to have less requirements for drug development in orphan disease.

The National Organization for Rare Disorders (NORD), is a unique federation of voluntary health organizations dedicated to helping people with rare "orphan" diseases and assisting the organizations that serve them. NORD is committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and service.

Everylife Foundation for Rare Diseases is an organization dedicated to accelerating biotech innovation for rare disease treatments through science-driven public policy. They have organized a series of rare disease workshops to facilitate the process and help guide improvements in the development process for rare disease treatments. The most recent workshop is on “Accelerated Approval for Rare Disease Treatments”. All presentation slides are posted for free. 

Additional references: