Improvements Needed in Clinical Testing of Anticancer Drugs

HRD-83-52: Published: Sep 26, 1983. Publicly Released: Oct 4, 1983.

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In response to a congressional request, GAO reviewed the clinical testing of anticancer drugs and the regulation of that testing by the Food and Drug Administration (FDA) to determine: (1) how well, during its review of new anticancer drug applications, FDA discharges its responsibility to protect human test subjects; (2) the manner in which drug sponsors and institutional review boards carry out their responsibilities; and (3) whether there is therapeutic intent during testing of anticancer drugs.

GAO found that FDA and the National Cancer Institute (NCI) have made some improvements to better ensure that patients involved in clinical testing of anticancer drugs are protected. These improvements include: (1) more monitoring of investigators who perform the clinical studies for the sponsors; (2) improved reporting of adverse drug reactions (ADR); and (3) increased controls over investigational new drug (IND) supplies. However, GAO believes that additional actions are needed. Delays by FDA reviewers in completing written reports on deficiencies resulted in FDA sending deficiency letters to sponsors 2 to 5 months after an application was received. GAO found instances where FDA was notified that its recommendations were not implemented because of a lack of a reporting system. Also, sponsors do not always submit amendments to FDA for review and, when they are submitted, FDA frequently does not review them or does not review them in a timely manner. GAO found 12 protocols involving five drugs that had not been submitted to FDA for review. FDA regulations are not specific regarding: (1) the definition of ADR; and (2) the time frames during which these reactions should be reported to FDA. In addition, it is difficult to determine in many instances whether a change in a patient's condition was caused by IND or by some other factor. Finally, GAO found that NCI does not require monitoring visits, but plans to expand the number of investigators visited.

Recommendations for Executive Action

  1. Status: Closed - Implemented

    Comments: Final regulations, containing this provision, were issued on March 19, 1987.

    Recommendation: The Secretary of Health and Human Services should require the Commissioner, FDA, to urge sponsors, if they have not already done so, to establish definite time frames for clinical investigator reporting of ADR, which will allow the sponsors time to meet FDA reporting requirements.

    Agency Affected: Department of Health and Human Services

  2. Status: Closed - Implemented

    Comments: Final regulations, containing this provision, were issued on March 19, 1987.

    Recommendation: The Secretary of Health and Human Services should instruct sponsors to label, or otherwise highlight, ADR forms or mailing envelopes to ensure that ADR will be recognized and dealt with immediately upon their arrival at FDA.

    Agency Affected: Department of Health and Human Services

  3. Status: Closed - Implemented

    Comments: NCI determined that there is a need for its drug study base and developed and implemented a computerized system for collecting data directly from clinical investigators in a uniform and timely manner. NCI also adopted a standardized reporting system for the few studies conducted without computer capabilities.

    Recommendation: The Secretary of Health and Human Services should require the Director, NCI, to review the need for and usefulness of its drug study database. If needed, NCI should require clinical investigators to submit data in a more timely and complete manner. If not needed, NCI should terminate the effort.

    Agency Affected: Department of Health and Human Services

  4. Status: Closed - Implemented

    Comments: The Department of Health and Human Services (HHS) completed action to ensure that NCI site visit monitoring includes all NCI investigators and now requires that drug shipments be made to satellite locations directly. However, HHS did not agree that its site visit frequency should be increased.

    Recommendation: The Secretary of Health and Human Services should require the Director, NCI, to: (1) ensure that NCI site visit monitoring includes all NCI investigators; (2) devise a procedure to verify investigators' drug disbursements to their satellite locations or require that drug shipments be made directly to these locations by NCI; and (3) if possible within allocated resources, increase the frequency of site visits to monitor investigators' performances.

    Agency Affected: Department of Health and Human Services

  5. Status: Closed - Implemented

    Comments: Final IND regulations, containing sponsor-monitoring responsibilities, were issued on March 19, 1987.

    Recommendation: The Secretary of Health and Human Services should require the Commissioner, FDA, to: (1) issue final sponsor-monitoring regulations; and (2) establish specific requirements for information to be included in progress reports submitted by sponsors of drug studies.

    Agency Affected: Department of Health and Human Services

  6. Status: Closed - Implemented

    Comments: In August 1983, FDA issued a memorandum to all appropriate management and reviewing staff stressing the need for documenting 30-day reviews.

    Recommendation: The Secretary of Health and Human Services should direct the Commissioner, FDA, to require that IND reviewers document for the record, within 30 days of the date an IND is submitted to FDA for initial review, that they have satisfied themselves as to the safety of patients participating in tests of new anticancer drugs.

    Agency Affected: Department of Health and Human Services

  7. Status: Closed - Not Implemented

    Comments: HHS did not agree that all deficiencies should be discussed with drug sponsors immediately because it does not consider all deficiencies to be of critical importance to patient safety.

    Recommendation: The Secretary of Health and Human Services should direct the Commissioner, FDA, to require that IND reviewers, whenever practical, discuss all IND deficiencies with sponsors before clinical testing begins, or promptly after a deficiency is noted if testing has already begun, and then communicate all such deficiencies in writing to the sponsor in a timely manner. To deal with situations where this procedure is not practicable, guidance should be developed to assist FDA reviewers in determining which deficiencies are sufficiently significant to be communicated promptly to test sponsors.

    Agency Affected: Department of Health and Human Services

  8. Status: Closed - Not Implemented

    Comments: HHS did not believe that the need for a formal follow-up system has been demonstrated. It has agreed to study the problem to see if a need exists.

    Recommendation: The Secretary of Health and Human Services should direct the Commissioner, FDA, to establish a formal follow-up system so that FDA can know whether IND sponsors respond to its recommendations to improve patient safety.

    Agency Affected: Department of Health and Human Services

  9. Status: Closed - Implemented

    Comments: Final IND regulations, containing these provisions, were issued on March 19, 1987.

    Recommendation: The Secretary of Health and Human Services should direct the Commissioner, FDA, to revise its regulations to require sponsors to approve and submit for FDA review, before clinical testing begins, all clinical protocols.

    Agency Affected: Department of Health and Human Services

  10. Status: Closed - Implemented

    Comments: Final IND regulations, requiring sponsors to clearly label IND amendments, were issued on March 19, 1987.

    Recommendation: The Secretary of Health and Human Services should direct the Commissioner, FDA, to develop a system for identifying major IND amendments and promptly distributing them to reviewers.

    Agency Affected: Department of Health and Human Services

  11. Status: Closed - Implemented

    Comments: Final IND regulations, containing these provisions, were issued on March 19, 1987.

    Recommendation: The Secretary of Health and Human Services should require the Commissioner, FDA, to give sponsors and clinical investigators more precise guidance as to what types of reactions they should report as ADR, and when they should report possible ADR in cases in which the reaction's relationship to the drug is uncertain. This should include specific time frames for reporting ADR to FDA.

    Agency Affected: Department of Health and Human Services

  12. Status: Closed - Not Implemented

    Comments: HHS contended that its channels of communication between NCI and FDA were sufficient.

    Recommendation: The Secretary of Health and Human Services should require the Director, NCI, to advise FDA in a timely manner of actions taken, or to be taken, on concerns raised by FDA during its review of NCI IND applications.

    Agency Affected: Department of Health and Human Services

 

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