Regulatory requirements in preparing for clinical trials

(Eric Bastings, FDA)

See FIG. 5 for an overview of the FDA regulatory process

The primary objectives of IND applications are to assure the safety and rights of subjects participating in the clinical trial.

  • The FDA also assesses the scientific quality of clinical trials and (for pivotal trials) the likelihood that the investigation will yield data capable of meeting the statutory standards for new drug approval.

An IND application is needed:

  • To give an investigational drug to humans in the U.S.
  • For a “lawfully marketed” drug product if the study is to support a label change, an advertising claim, or will significantly increase the risk of the product.
    • If a study of a “lawfully marketed” drug does not fall into these categories, then it is exempt from an IND application. An investigator or the FDA can make that decision.
    • Once judgment is made of whether or not exemption criteria are met, an IND cannot be accepted.

IND application (312.23) components:

  • Table of contents
  • Introductory statement/general investigation plan
  • Investigator’s brochure
  • Proposed study protocol
  • Adequate CMC data
  • Non-clinical data sufficient to support the proposed protocol
  • If not first in human study, summary of prior human experience (e.g. non-U.S)

Commercial vs. research (academic investigator) IND

  • The overall requirements are the same.
  • Research INDs commonly use marketed drug products, so CMC and non-clinical data are already “covered” by an approved NDA (include copy of drug package insert).
  • If single site, the investigator’s brochure not needed for research INDs
  • Submission must follow FDA IND format and not NIH grant submission format

Investigator’s brochure

  • Brief product description
  • Pharm/tox summaries
  • Previous human experience
  • Description of anticipated risk and any special monitoring needs
  • Updates as appropriate
  • Must be provided to each clinical investigator (but not required for single site research INDs)

Clinical protocols

  • Regulations for Phase 1 protocols suggest that the protocol may be “incomplete” – the FDA still expects it to be detailed.
  • Provide (safety) rationale for doses, in relation to preclinical animal studies.
  • Expect intensive monitoring for sufficient duration (in-house for NMEs), with adequate follow-up of participants after the administration of the drug.
  • Phase 2/3 protocols must include primary (and secondary) endpoints plus a more detailed analysis plan

Expected elements in a protocol

  • Investigational plan:
    • Study design
    • Study population (inclusion and exclusion criteria)
    • Treatments (including description of doses, timing, blinding, prior and concomitant therapies, assessment of compliance)
    • Efficacy and safety variables with visits schedule (and flow chart)
  • Safety monitoring:
    • Methods for reporting adverse events
    • Stopping rules
      • Common Toxicity Criteria (CTC) usually not appropriate.
      • Specific rules may be warranted for known or expected toxicities.
      • It is impossible to have rules for all possible unexpected toxicities; good judgment is usually preferred to a “global rule” which is often unacceptable (e.g. “stopping for 2 or more patients with grade 3 toxicities”).
    • Data and safety monitoring board
    • Handling of pregnancies

Safety reporting – new IND rule effective March 28, 2011

  • More fully defines the responsibilities of sponsors and investigators (specifically, submission of serious and unexpected suspected adverse reactions)
  • Implements internationally harmonized definitions and reporting standards.
  • A suspected adverse reaction is any adverse event for which there is a reasonable possibility that the drug caused the adverse event. “Reasonable possibility” means there is evidence to suggest a causal relationship between the drug and the adverse event
  • An adverse event is considered unexpected if the event is:
    • Not listed in the IB
    • Not listed at the severity that has been observed
    • Mentioned in the IB as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but not mentioned with the drug under investigation
  • An adverse event is considered serious if any of the following outcomes occur:
    • Death
    • Life-threatening events (immediate risk of death)
    • Inpatient hospitalization or prolongation of hospitalization
    • Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
    • Congenital anomaly or birth defect
    • “Important medical events” that may lead to the outcomes described above
    • Seriousness determination is based on the opinion of either the investigator or sponsor (if either believes it is serious, it must be considered serious).
  • Sponsors must submit an expedited report of any suspected adverse reaction that is both serious and unexpected – the even must meet all three criteria (suspected adverse event, unexpected, serious).
  • Sponsors submit expedited reports only if there is evidence to suggest a causal relationship between the drug and the adverse event. Examples of causal evidence:
    • Individual occurrences – Single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g. angioedema, hepatic injury, Stevens-Johnson syndrome).
    • One or more occurrences – Single occurrence or a small number of occurrences of an event that is not commonly associated with drug exposure but is otherwise uncommon in the population exposed to the drug (e.g. tendon rupture).
    • Aggregate analysis of specific events – Events occur more frequently in the drug treatment group than in a concurrent or historical control group (e.g. known consequences of underlying disease, events common in the study population).

Other new expedited reporting requirements:

  • Report study endpoints (e.g. mortality, major morbidity) as described in the protocol, not in an IND safety report.
    • Exception: If there is evidence suggesting a causal relationship (e.g. death from anaphylaxis in a trial with an all-cause mortality endpoint).
  • Report increased rate of serious suspected adverse reactions over that listed in the protocol or investigator brochure.
  • Report findings that suggest a significant human risk.
    • From clinical, epidemiological or pooled analysis of multiple studies
    • From animal or in vitro testing (e.g., mutagenicity, teratogenicity, carcinogenicity)
    • Usually results in a safety-related change in the protocol, IB, and/or informed consent

Changes in investigator reporting

  • Old rules
    • Must promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by the drug.
    • If the adverse effect is alarming, the investigator shall report the adverse effect immediately.
  • New rules
    • Must immediately report any serious adverse event to the sponsor, including those listed in the IB or protocol (except study endpoints).
    • Include an assessment of whether there is a reasonable possibility that the drug caused the serious adverse event.
    • Non-serious adverse events are recorded and reported to sponsor according to protocol.

Reporting timeframes (for sponsors)

  • Report to be made within 15 calendar days after the sponsor determines that the suspected adverse reaction or other information qualifies for reporting.
  • If FDA requests any additional data or information, submit as soon as possible but no later than 15 calendar days after receiving the request.
  • Unexpected fatal or life-threatening suspected adverse reactions (7-day) – Report within 7 calendar days after sponsor’s initial receipt of the information.
  • Follow-up reports – Report as soon as information is available.

Clinical holds

  • If no hold is imposed after 30 days, the study may proceed.
  • Possible reasons for hold:
    • Unreasonable/significant risk of injury
    • Clinical investigators unqualified
    • IB misleading, erroneous, or incomplete
    • Insufficient information to assess the risks
    • Exclusion by gender for life-threatening disease
  • Nonclinical deficiencies resulting in clinical hold:
    • Lack of studies
    • Lack of adequate documentation (e.g., individual animal line listings)
    • Inadequate doses (justification not provided)
    • No no-effect dose for unacceptable toxicity
  • If the FDA imposes a clinical hold:
    • You will typically be told via telephone call.
    • You will be told before or on day 30.
    • The call will briefly discuss the basis for the hold and identify which studies are on hold.
    • Detailed letter to follow within 30 days.
  • If on hold, the investigation may not resume until we have notified you that it may proceed.
    • The mechanism to correct the hold deficiencies is submission of a “clinical hold complete response” – this is a formal submission to the IND that addresses the issues in the hold letter.
    • Upon receiving a complete response, the FDA will:
      • initially determine if it is a complete response.
      • review it within 30 days and notify you in writing whether the clinical hold is removed or maintained.
      • Unlike an initial IND submission, once on hold, you may NOT proceed with the trial even if you haven’t heard from the FDA within 30 days
  • To avoid a clinical hold:
    • Lower starting dose
    • Lower maximum dose
    • Limit on plasma levels permitted
    • Slower titration
    • More subjects/group
    • Better monitoring (e.g. specific tests, longer in-patient surveillance)
    • Shorter treatment period

Meetings with the FDA

  • Meetings are typically held with commercial sponsors and are primarily designed to help in the development of new drugs.
    • The FDA also meets with academic sponsors, especially if they are proposing a “definitive” trial, typically in an orphan disease which may be considered “pivotal”.
  • Pre-IND meetings are intended to expedite the development of drugs for the treatment of life-threatening and severely-debilitating illnesses, especially where no satisfactory alternative therapy exists. Goals of pre-IND meetings:
    • To review and reach an agreement on the design of animal studies needed to initiate human testing
    • To discuss the scope/design of phase 1 testing
    • To discuss pediatric evaluation plans
    • To discuss the best approach for the presentation and formatting of data in the IND
    • To discuss safety issues for human non-IND studies done outside the U.S.
  • Meeting package content
    • Product name, indication, dosage form/regimen
    • List of sponsor attendees
    • Product background
    • Summary of meeting purpose
    • Proposed agenda
    • List of questions grouped by discipline
    • Data to support discussion, organized by discipline and question (must be concise)
  • Meeting can be in person or by teleconference.
    • Preliminary answers to your questions sent 1-2 days before the meeting.
    • Only issues for which there remains a need for clarification should be discussed.
    • Final meeting minutes sent within 30 days after meeting.
  • See Resources – FDA Meetings Guidance PDF
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