Tuesday, July 15, 2014

Pre-screening procedures in clinical trials

For typical clinical trials, the study design will include a screening period before the randomization / start of the study medication. The purpose of the screening period is to make sure that only subjects who meet the inclusion/exclusion criteria are included in the study. The screening period usually starts from the informed consent signing to the randomization or the start of the study medication.

In some situations, depending on the timing of the informed consent and the randomization, a pre-screening period may be needed. For a study with both pre-screening and screening periods, the pre-screening period will filter out majority of those subjects who may not meet a simple inclusion criteria for the study before the formal screening procedures are performed. In this way, the screening failure rate can be significantly lowered. It is typical that the pre-screening results may be recorded on a pre-screening log, but not necessarily recorded on the study case report form, which will minimize the burden on the data recording for screen failure subjects if the screening failure rate is too high.

1) pre-screening is performed prior to the formal screening procedures are performed.
2) with pre-screening process, there will actually be two steps for screening the subjects for the study.
3) depending on what kind of pre-screening procedures are performed, the pre-screening may or may not require the informed consent from the patients.
4) if the consent is required for pre-screening, there will be two informed consents for the study: one for pre-screening and one for formal screening.
5) the results from pre-screening may be recorded in a pre-screening sheet instead of the case report forms. This is especially true if the pre-screening only involves reviewing of the patient medical charters and the review of the non-study specific test results. In this way, we can minimize recording the large amount of data for pre-screening failure subjects, which is not be valuable to the objectives of the clinical study.

In PROACT II study, in order to have 180 subjects eligible for randomization, 12323 stroke patients were screened. It will be a disaster if we consent all 12323 patients and record the information for all 12323 patients. Here a pre-screening process will be very useful. Since the pre-screening procedures involves only the non-study specific procedures (these procedures will be performed for any stroke patients anyway), there is no separate informed consent needed.

There is no formal regulatory guidance on the pre-screening procedure, however, the FDA’s opinion can be seen in “Screening Tests Prior to Study Enrollment - Information Sheet -Guidance for Institutional Review Boards and Clinical Investigators
For some studies, the use of screening tests to assess whether prospective subjects are appropriate candidates for inclusion in studies is an appropriate pre-entry activity. While an investigator may discuss availability of studies and the possibility of entry into a study with a prospective subject without first obtaining consent, informed consent must be obtained prior to initiation of any clinical procedures that are performed solely for the purpose of determining eligibility for research, including withdrawal from medication (wash-out). When wash-out is done in anticipation of or in preparation for the research, it is part of the research.
Procedures that are to be performed as part of the practice of medicine and which would be done whether or not study entry was contemplated, such as for diagnosis or treatment of a disease or medical condition, may be performed and the results subsequently used for determining study eligibility without first obtaining consent. On the other hand, informed consent must be obtained prior to initiation of any clinical screening procedures that is performed solely for the purpose of determining eligibility for research. When a doctor-patient relationship exists, prospective subjects may not realize that clinical tests performed solely for determining eligibility for research enrollment are not required for their medical care. Physician-investigators should take extra care to clarify with their patient-subjects why certain tests are being conducted.
Clinical screening procedures for research eligibility are considered part of the subject selection and recruitment process and, therefore, require IRB oversight. If the screening qualifies as a minimal risk procedure [21 CFR 56.102(i)], the IRB may choose to use expedited review procedures [21 CFR 56.110]. The IRB should receive a written outline of the screening procedure to be followed and how consent for screening will be obtained. The IRB may find it appropriate to limit the scope of the screening consent to a description of the screening tests and to the reasons for performing the tests including a brief summary description of the study in which they may be asked to participate. Unless the screening tests involve more than minimal risk or involve a procedure for which written consent is normally required outside the research context, the IRB may decide that prospective study subjects need not sign a consent document [21 CFR 56.109(c)]. If the screening indicates that the prospective subject is eligible, the informed consent procedures for the study, as approved by the IRB, would then be followed.
Certain clinical tests, such as for HIV infection, may have State requirements regarding (1) the information that must be provided to the participant, (2) which organizations have access to the test results and (3) whether a positive result has to be reported to the health department. Prospective subjects should be informed of any such requirements and how an unfavorable test result could affect employment or insurance before the test is conducted. The IRB may wish to confirm that such tests are required by the protocol of the study.
In a document issued by partners.org, it stated that the pre-screening information can be recorded on pre-screening sheets.
V. Retaining Information from Individuals who are Pre-Screened but not Enrolled
It is acceptable to retain non-identifying information about individuals who are pre-screened for a study, but do not actually pursue the study or enroll. In fact, this is often desirable or even requested by industrial or academic sponsors to obtain information about the entire pool of individuals interested or potentially eligible for the study. Pre-screening sheets from individuals who did not provide identifying information can be retained with no further action. Pre-screening sheets with identifying information gathered to obtain written authorization and prior to enrollment (signing of informed consent form) may also be retained in research files, but must have segments containing identifiable information blacked out or cut off as soon as it is clear that the individual will not be enrolled. If identifiable health information is to be retained, the investigator must obtain an authorization from each of the persons screened.
Separating the pre-screening and screening periods may have different purpose. For example, in an IBS-D study, both prescreening and screening periods are included in the study. The informed consent would be required for the pre-screening since the pre-screening procedures are beyond the typical patient care. The formal screening process was to establish the baseline since the baseline measure requires recording the daily symptom over 7-14 day period.
“this study consisted of an initial prescreening period, a screening period of 2 to 3 weeks, a 12-week double-blind treatment period, and a 2-week post-treatment period. During the 1-week prescreening period, patients underwent a physical examination, provided blood and urine for routine testing, and discontinued any prohibited medications. Patients who met the inclusion and exclusion criteria entered the screening period and began using an interactive voice response system (IVRS) to provide daily symptom assessments. After the screening period of 2-3 weeks, patients who continued to meet eligibility criteria and were compliant with the IVRS system for at least 6 of 7 days during the week before and 11 of 14 days during the 2 weeks before were randomized in parallel…..”

Saturday, July 12, 2014

Clinical Trial Registries in US, EU, WHO, China, and other countries

For the past decade, there was increasing pressure on pharmaceutical companies to be transparent on the clinical trials and the clinical trials results. It is considered not a good practice if the pharmaceutical companies publish only the clinical trial with positive results and hide the clinical trial with negative results.

On September 27, 2007, the President George W Bush signed U.S. Public Law 110-85. The law includes a section on clinical trial databases (Title VIII) that expands the types of clinical trials that must be registered in ClinicalTrials.gov, increases the number of data elements that must be submitted, and also requires submission of certain results data.

After the law is enacted, the clinical trial registries have blossomed. In US, all clinical trials are required to be registered in clinicaltrials.gov database. In EU countries, the clinical trial registries should be registered on https://www.clinicaltrialsregister.eu/.

In the early stage, some companies used a perfunctory way in compliant with the registries and provided very little or meaningless information on the clinical trial registries. For example, one of the clinical trial entry listed Primary Outcome Measures ‘Efficacy’; Secondary Outcome Measures ‘Safety’ instead of providing what the outcomes are.

With the time, the companies are now more serious about the clinical trial registries. For those companies who are not compliant with clinical trial registries, there are penalties.
“FDAAA 801 establishes penalties for Responsible Parties who fail to comply with registration or results submission requirements. Penalties include civil monetary penalties and, for federally funded studies, the withholding of grant funds.

See the statutory provisions amending Civil Money Penalties (PDF) and Clinical Trials Supported by Grants From Federal Agencies (PDF). “
More importantly, the clinical trial registration is now becoming a requirement for the publication. For medical journal, it will be difficult to get clinical trial results published if the study is not registered at the time of the clinical trial start. International Committee of Medical Journal Editors (ICMJE) indicated that the following registries are acceptable
There are many other registries that meet specific criteria for content, quality and validity, accessibility, unique identification, technical capacity and administration established by WHO. Primary Registries meet the requirements of the ICMJE.

ICMJE also stated:
“In addition to the above registries, starting in June 2007 the ICMJE will also accept registration in any of the primary registries that participate in the WHO International Clinical Trials Portal (see http://www.who.int/ictrp/network/primary/en/index.html). Because it is critical that trial registries are independent of for-profit interests, the ICMJE policy requires registration in a WHO primary registry rather than solely in an associate registry, since for-profit entities manage some associate registries. Trial registration with missing or uninformative fields for the minimum data elements is inadequate even if the registration is in an acceptable registry.”
The same clinical trial may be registered in multiple clinical trial databases, but is not required to be registered in multiple clinical trials databases. In reality, we often found that the same clinical trials are registered in multiple places and the data entries are for the same trial are actually different in different registries.

In 2013, SFDA of China issued the regulation '关于药物临床试验信息平台的公' requiring the clinical trial registration at http://www.chinadrugtrials.org.cn/ on its platform at www.cde.org.cn.