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ISSN 1369-9407


FDA warning letter outlines multiple violations

Details of the adverse findings from US Food and Drug Administration (FDA) inspections are available in the form of warning letters. FDA warning letters are issued to clinical investigators, sponsors and institutional review boards (IRBs) when unacceptable violations of the regulations are discovered. Examination of the findings contained in warning letters provides useful guidance to other investigators and sponsors performing clinical trials, not just in the USA but elsewhere, as many of the deficiencies occur globally. In this special issue we review the warning letter sent to an investigator in California, USA, after an FDA inspection revealed serious violations of informed consent, protocol deviations, inadequate record keeping and failure to ensure continuing ethics review. dated 1 May 2008, emphasising the findings outlined below.

Violations of informed consent

Subjects may not be enrolled in a clinical trial unless the investigator has obtained legally effective informed consent from the subject or their legally authorised representative. Typically, informed consent must be given on a written consent form approved by the IRB. However, during the inspection the FDA found that · protocol-specified baseline laboratory blood samples were obtained from four out of 23 subjects before they had signed and dated the informed consent document · there was no documentation of the time when informed consent was obtained, despite this being a requirement of the IRB-approved informed consent document. The FDA could not verify that subjects signed and dated the informed consent document prior to undergoing protocol-specified procedures. The investigator responded that in all cases the subject had given verbal consent prior to any study procedures being performed. page 2

The inspection

In summer 2007, an FDA inspector visited a clinical investigator in California, USA, involved in clinical trials in acute bacterial sinusitis, community-acquired pneumonia and chronic bronchitis. The inspection was part of FDA's Bioresearch Monitoring Program designed to evaluate the conduct of research and to ensure that the rights, safety and welfare of human subjects have been protected. From the establishment inspection report, the documents submitted with the report and a letter written by the investigator in September 2007 in response to Form FDA 483, Inspectional Observations, the FDA concluded that the investigator did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical trials and the protection of human subjects. A warning letter followed,

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CRAdvisor, Issue 224, 2008



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This is clearly inadequate. [Violation of 21 CFR 312.60]

Lessons to be learnt

It is not uncommon to find that investigators have screened potential subjects and undertaken assessments described in the protocol before the subject has given informed consent. Investigators often think that this is a legitimate practice as they are only undertaking screening, and no harm is done as they have not administered investigational product. It is important that sponsors adequately brief investigators prior to the study commencing and stress that any procedure described in the protocol cannot be undertaken until informed consent has been obtained. Auditors and inspectors look carefully at this aspect. A clear audit trail of documentary evidence should demonstrate the day (and even the time when relevant) that consent was obtained and this should precede the date/time of any trial-related procedures. An extract from the Federal Register on the timing of consent forms is given at the end of this article.

clinical signs and symptoms highly suggestive of acute bacterial sinusitis and would have been treated with antibiotics regardless of enrolment in the study. The FDA points out that this response is inadequate, stating that the regulations require investigators to follow the investigational plan to help ensure that data collected during the study are reliable and that the rights, safety and welfare of research participants are protected.

Lessons to be learnt

It is inevitable that protocol violations will occur in a clinical trial. However, investigators should try hard to ensure that protocol violation is avoided. This can be done by exercising care and diligence. Careful briefing of the requirements of the protocol should be undertaken by the sponsor's monitor. There are no excuses when an investigator fails to undertake assessments relevant to entry criteria and the effectiveness of the treatment at the end of the study. Although the investigator can argue that a clinical diagnosis was sufficient ­ and that is probably true in a normal clinical situation ­ it needs to be made clear at the briefing that once the protocol is agreed and signed it defines the procedures to be followed. Extra processes are often required as trial data need to be more evidential. The number and nature of protocol violations can be used as a measure of the quality and reliability of the data and the investigator's performance. If the investigator fails to follow basic rules, can the sponsor and regulators be sure that something more serious (eg. an adverse reaction) has not been missed? One of the other studies specified that subjects who withdrew prematurely were to undergo a complete clinical assessment, and to have a sputum specimen collected and all safety laboratory investigations performed. Furthermore, if an alternative antimicrobial agent was prescribed, testing was to be performed before treatment with the alternative agent. These subjects were also to undergo a clinical assessment 2­4 days after the last dose of therapy with the alternative antibiotic. Two subjects were

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Deviations from study protocol

Several deviations from the approved protocol for the acute bacterial sinusitis study were noted: · subjects were to have a clinical diagnosis of acute sinusitis with signs and symptoms present for more than 7 but less than 28 days, as defined by radiographic and clinical criteria. However, 10 out of the 30 enrolled subjects failed to meet the protocol-required radiographic documentation for inclusion in the study; specifically, X-rays for these subjects did not show acute sinusitis. · subjects who had received systemic antimicrobial agents for more than 24 hours within 7 days prior to enrolment were to be excluded from the study. One subject was enrolled in the study even though s/he had been taking doxycycline during this exclusionary time period. · for nine out of 30 subjects, a paranasal view X-ray was not obtained at the Test of Cure visit, despite being required by the protocol. The investigator responded that the patients all had

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prematurely withdrawn from the study but did not have sputum collected or a complete post-alternative clinical assessment. Several violations were noted for the remaining study protocol: · the amended protocol specified that for a course of therapy to be microbiologically valid, study inclusion required at least one causative organism to be identified in an appropriate pre-treatment sputum specimen; a subsequent amendment further clarified this inclusion criterion. However, two subjects were enrolled in the study even though their sputum samples did not meet the inclusion criterion with regard to the causative organism. · at the time of enrolment, a medical history was to be obtained, including past history of respiratory illnesses, smoking history, an inquiry regarding any underlying illness or conditions, and general health status. A complete medical history was not obtained for all subjects. · two subjects did not undergo the baseline urinalysis test as required by the protocol. · 48 hours prior to enrolment, subjects were to provide a purulent or muco-purulent sputum specimen by deep expectoration; one subject was unable to produce the specimen but was still dispensed study medication. · at the Test of Cure visit, subjects were to have a serum pregnancy test, but at least one subject did not have this test. The investigator's written response noted that patients coming into the office with an acute infection need to be treated quickly and that study subjects had to be screened, enrolled and randomised in a way that was typically much faster than for non-infectious disease clinical trials. As a result, there was no in-depth review of screening with all laboratory and X-ray data at hand before randomisation. The FDA considered this response inadequate, stating that the regulations require investigators who enrol subjects into FDA-regulated clinical studies to follow the investigational plan, to help ensure the reliability of data collected during the study and that the rights, safety and welfare of subjects are protected. [Violation of 21 CFR 312.60]

Lessons to be learnt

It is desirable for investigators to have some input into the protocol. The aim of this process is to ensure that the methodology and logistics are practical. It is at this point that the investigator should have raised the issues of timing. Even if the study was started and it was later found that the schedules were impractical, it was appropriate for the investigator to have raised this with the sponsor to consider a course of action to alleviate the difficulties. The problems should have been documented in a file note. Overall, once problems of protocol violation have been detected at a site, it is wise for the sponsor to monitor the study more frequently to ensure that further violations are detected quickly. The sponsor should also re-brief investigator team members of measures put into place to prevent violations.

Inadequate record keeping

Record keeping is a fundamental part of both routine clinical practice and clinical trial conduct, but the FDA noted that this investigator had violated FDA regulations relating to the maintenance of adequate records. · The clinical signs and symptoms of disease reported in the electronic case report form (CRF) for one protocol could not be verified against information within the source documents for 17 out of 30 subjects enrolled in the study, all of whom were enrolled prior to 12 February 2001. A Memorandum to File dated 12 February 2001 was found during the FDA inspection, which noted that for all study visits up to 12 February 2001 all specific sinusitis symptoms and the subsequent ratings entered in the system have "on occasion no supporting documents". The Memorandum to File went on to state that, "Going forward, all specific sinusitis symptoms, or any visit specific data entered into the system shall have supporting documents". · There was a discrepancy between the CRF and the source documentation for the baseline clinical signs and symptoms of disease at the pre-therapy visit for one enrolled subject. On 12 April 2001, the investigator signed and dated a change to the CRF,

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which noted that the subject had moderate and not mild wheezing. However, the source document for the pre-therapy visit on 24 January noted that the subject had increased wheezing at the visit, but it did not note the extent of the wheezing. · The Inventory Drug Disposition Log for one subject listed the number of tablets returned on 30 December 2000 as 15, while the electronic CRF listed the number as 12. [Violation of 21 CFR 312.62(b)]

amendment. The investigator was therefore considered to have failed to demonstrate that the change was promptly reported to the IRB. [Violation of 21 CFR 312.66]

Lessons to be learnt

The trial sponsor could have made greater effort to ensure that the investigator followed the requirements once they had agreed the protocol amendment. The sponsor could have asked for a copy of the IRB approval of the protocol amendment before it authorised the implementation of the change. The investigator should have been aware of the need to ensure that all documentation is in place, and carefully filed in the study master file. This again suggests that the investigator lacks experience and is not fully aware of the regulations. More extensive checks on the suitability of the investigator as well as comprehensive training prior to the start of the study might have avoided many of the problems reported here. As is usual when a warning letter is issued, the investigator was given 15 working days from receipt of the warning letter to notify the Center for Drug Evaluation and Research, in writing, of the actions taken or planned to be taken to prevent similar violations in the future. The investigator was also warned that failure to explain adequately and promptly the violations noted may result in regulatory action without further notice. The FDA expects the responses to be detailed and well considered and, to minimise ongoing problems, it is worth investigators and sponsors seeking advice from those experienced in providing responses to the FDA.

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Lessons to be learnt

In combination with the failure to adhere to the investigational plan, the lack of adequate source documentation and/or record keeping gives rise to the opinion that this investigator is not taking seriously his/her responsibilities. The cause of the problem needs investigation by the sponsor. Is it due to the investigator being inexperienced and not understanding the requirements? Is it because there has been delegation of responsibility to uninterested, incapable or poorly briefed team members? Is it because everyone is too busy to perform the trial properly? Whatever the reason, the sponsor's monitor should identify the cause and then suggest corrective and preventative remedies. Failure of the investigator to perform the study in accordance with the protocol may render the trial unethical and jeopardise subject safety.

Lack of continuing IRB review

Federal regulations require clinical investigators to make sure that all changes in the research activity are promptly reported to the IRB. A protocol amendment was made on 16 October 2000, but during the FDA inspection the investigator did not provide a copy of the IRB approval of this

Federal Register: November 5, 1996 (Volume 61, Number 215, page 57278)

Extract on the dating and timing of consent forms: "The agency agrees that when, for example, the consent form is signed on the same day that the subject begins participation in the study, it may not be able to verify from a dated consent form that consent was obtained prior to an individual's participation in the research; therefore, other documentation may be needed. However, the agency does not think that it is appropriate to require the time of signature to be included on every consent form in order to permit this verification".

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Extracts from the relevant Code of Federal Regulations

The quoted extracts from the regulations were updated on 1 April 2007 and were current versions on the FDA website on 22 June 2008.

21 CFR 50.20

General requirements for informed consent. Except as provided in 50.23 and 50.24, no investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence.

chapter. Additional specific responsibilities of clinical investigators are set forth in this part and in parts 50 and 56 of this chapter.

21 CFR 312.62

Investigator recordkeeping and record retention. (a) Disposition of drug. An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug under 312.59. (b) Case histories. An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study. (c) Record retention. An investigator shall retain records required to be maintained under this part for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being

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21 CFR 312.60

General responsibilities of investigators. An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator's care; and for the control of drugs under investigation. An investigator shall, in accordance with the provisions of part 50 of this chapter, obtain the informed consent of each human subject to whom the drug is administered, except as provided in 50.23 or 50.24 of this

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investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified.

Principal Author & Editor: Prof David Hutchinson Senior Writers: Jane Baguley, Gareth Griffiths Production Editor: Sharon Jordan Correspondents:

Joris Bannenberg Gitte Raaschou Beck Fabio Camarri Pamela Charnley Nickols Paul Chester Eugen Chicevic Sheelagh Corcoran Nigel Dent Gerhard Fortwengel Hideki Fujiwara Maria Galikova Francois Geelen Yves Geysels Lisbeth Tofte Hemmingsen Irene Herod Ilian Ivanov Ezequiel Klimovsky Tina S Klint Bettina Klesse Paul Marcus Julie Meeson John Parker Daniela Sima Sam Tong Colin Wilsher

21 CFR 312.66

Assurance of IRB review. An investigator shall assure that an IRB that complies with the requirements set forth in part 56 will be responsible for the initial and continuing review and approval of the proposed clinical study. The investigator shall also assure that he or she will promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others, and that he or she will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.

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