3.9 Contraception Requirements

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• 3.1. For FDA approved drugs which comply with FDA Pregnancy and Lactation Labeling Rule (PLLR), categories are determined by the investigator and are based on data in FDA approved “Prescribing Information” (especially sections 8.1 [Pregnancy] and 8.3 [Females and Males of Reproductive Potential]).
• 3.2. For drugs not approved by the FDA, or approved drugs that do not comply with the PLLR, categories are determined by the investigator and are based on information in the Investigator’s Brochure related to teratogenicity and genotoxicity, and/or on the published medical literature, and/or on the FDA Use in Pregnancy Category.
• 3.3. Categories
  • 3.3.1. Group 1: No systemic absorption of drug or biologic.
  • 3.3.2. Group 2: Review of clinical trials conducted in pregnant women,persons, pregnancy exposure registries, and other large scale epidemiologic studies show no evidence of adverse developmental outcomes.
    • 3.3.2.1. This would include drugs with FDA Use in Pregnancy category A.
  • 3.3.3. Group 3: In the absence of human data, animal studies show no evidence of adverse developmental outcomes.
    • 3.3.3.1. This would include drugs with FDA Use in Pregnancy category B.
  • 3.3.4. Group 4: Animal studies show evidence of adverse developmental outcomes, at dose levels higher than those to be used in this study.
  • 3.5. Group 5:
    • 3.3.4.1. This might include some drugs in FDA Use in Pregnancy category C, depending on dose levels.
  • 3.3.5.1. Group 5: (1) Review of clinical trials conducted in pregnant women,persons, pregnancy exposure registries, other large scale epidemiologic studies, or well described case-series show evidence of adverse developmental outcomes; OR
  • (2) 3.5.2. Animalanimal studies show evidence of adverse developmental outcomes, at dose levels similar to those to be used in this study; OR
  • (3) 3.5.3. Thethe mechanism of action of the drug suggests the possibility of adverse developmental outcomes.outcomes
    • 3.3.5.1. This might include some drugs in FDA Use in Pregnancy categories C (depending on dose levels), D and X

4.0 DefinitionsAllowable Contraception Requirements

• 4.1. Investigators may or must require contraception in accordance with data driven and good faith estimates of the FDAlikelihood Use-In-Pregnancyof Categoriesfetal
  injury
  • due 4.1. Category A: Controlled studies show no risk: Adequate, well-controlled studiesto in pregnantutero women have failed to demonstrate a riskexposure to the fetusdrug inas anyfollows: trimester of pregnancy.
  • 4.1.1. 4.2.Studies CategoryInvolving B:Group No1 and Group 2 Drugs {no evidence of risksystemic in humans Adequate, well-controlled studies in pregnant women have not shown increased riskabsorption of fetaldrug abnormalities(group despite adverse findings in animals nor, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote, but remains a possibility.
  • 4.3. Category C: Risk cannot be ruled out: Adequate, well-controlled human studies are lacking, and animal studies have shown a risk to the fetus1), or are lacking as well. There is a chance of fetal harm if the drug is administered during pregnancy; but the potential benefits may outweigh the potential risk.
  • 4.4. Category D: Positiveno evidence of risk:adverse Studiesdevelopmental in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective.
  • 4.5. Category X: Contraindicated in pregnancy: Studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk that clearly outweighs any possible benefit to the patient.

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  5.0 Procedure

  • 5.1. For drugs or biologics for which there is Pregnancy and Lactation Labelling availableoutcomes (allgroup investigational2)} drug- applicationsThe submitted after 6/30/2015, and all approved drugs for which Pregnancy and Lactation Labelling has been submitted and approved by FDA), the ICFs must include the appropriate standard contraception language based upon the categories in section 3.0 (see Addendum 1 attached at the end of this policy).
    • 5.1.1. Studies Involving Group 1 Drugs
      • 5.1.1.1. Protocolprotocol may not require use of contraception.
      • 4.1.2. Studies involving Group 3 Drugs {No human data but animal studies show no evidence of adverse developmental outcomes} - The protocol may require the use of ONE form of effective contraception; this may include (but may not require) the use of a form of highly effective contraception.
      • 4.1.3. Studies involving Group 4 Drugs {Animal studies show evidence of adverse developmental outcomes, at dose levels higher than those to be used in this study} - The protocol must require the use of ONE highly effective form of contraception, or TWO concurrent forms of effective contraception.
      • 4.1.4. Studies involving Group 5 Drugs {evidence of adverse developmental outcomes; OR mechanism of action of the drug suggests the possibility of adverse developmental outcomes} - The protocol must require the use of TWO forms of concurrent contraception, at least one of which must be highly effective.
    • 4.2. Highly effective forms of contraception (<1 pregnancy per 100 person-years) include long-acting reversible contraception (LARCs), copper or hormonal IUD, or tubal ligation.
    • 4.3. Effective forms of contraception (6-12 pregnancies per 100 person-years) include injectable, oral, transdermal or local (vaginal) hormonal therapy, double barrier methods, diaphragm plus spermicide, or other single barrier methods plus spermicide.
    • 4.4. Persons who practice total abstinence, when this is in line with the preferred and usual lifestyle of the subject may participate in research without requiring the use of contraception. Total abstinence does not include methods of “periodic abstinence” (such as calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal.
      • 4.4.1. Persons not participating in sexual activities that could lead to pregnancy (including but not limited to total abstinence in line with their preferred and usual lifestyle) may be required to utilize barrier or double barrier contraception as above should they deviate from this preferred and usual lifestyle.
    • 4.5. Persons who are not of reproductive potential (premenarchal, postmenopausal, or surgically or otherwise sterile) are eligible to participate in research without requiring the use of contraception.
    • 4.6. Exceptions to this policy must be approved by the full IRB after adequate justification by the PI.

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  • 5.0 5.1.2.Additional Studies involving Group 2 Drugs (Human data shows no evidence of adverse developmental outcome)Requirements

    • 5.1.2.1. The protocol may require the use of ONE form of contraception, with IRB approval, after justification by the PI.
  • 5.1.3. Studies involving Group 3 Drugs (Animal Data shows no evidence of adverse developmental outcome)
    • 5.1.3.1. The protocol may require the use of ONE form of contraception, with IRB approval, after justification by the PI.
  • 5.1.4. Studies involving Group 4 Drugs (Animal studies show evidence of adverse developmental outcomes, at dose levels higher than those to be used in this study)
    • 5.1.4.1. The protocol must require the use of ONE or TWO form(s) of concurrent contraception.
  • 5.1.5. Studies involving Group 5 Drugs (Animal or Human studies show evidence of adverse developmental outcomes, or drug mechanism of action suggests the possibility of adverse developmental outcomes)
    • 5.1.5.1. The protocol must require the use of TWO forms of concurrent contraception.
  • 5.1.6. For all groups, the ICF must utilize the appropriate standard language.
  • 5.1.7. The duration of contraception must be stated in the IRB Application and in the ICF. If contraception is required for longer than the time the drug is being administered, justification must be provided.
  • 5.2. For drugs or biologics for which Pregnancy and Lactation Labeling is not available, the ICFs must include the appropriate standard contraception language based upon the categories in section 4.0 (see Addendum 1 attached at the end of this policy).
    • 5.2.1. Studies Involving Category A Drugs:
      • 5.2.1.1. Protocol may not require use of contraception. Exceptions to this policy must be approved by the full IRB after adequate justification by the PI.
    • 5.2.2. Studies Involving Category B Drugs:
      • 5.2.2.1. The protocol may require the use of ONE form of contraception, with IRB approval, after justification by the PI.
    • 5.2.3. Studies Involving Category C Drugs:
      • 5.2.3.1. The protocol must require the use of ONE or TWO form(s) or concurrent contraception.
    • 5.2.4. Studies Involving Category D Drugs:
      • 5.2.4.1. The protocol must require the use of TWO forms of concurrent contraception.
    • 5.2.5. Studies Involving Category X Drugs:
      • 5.2.5.1. The protocol must require the use of TWO forms of concurrent contraception.
  • 5.3. For all groups and categories described above, the ICF must useinclude the corresponding standard Contraception language in Addendum 1,1, except:
    • 5.3.2.1. For Group 5 drugs, or category D or X drugs, if the sponsor mandates specific contraception language be included in the ICF this language may be used in lieu of the standard language in Addendum 1,1, provided the IRB determines that the specified language is as protective of the potential fetus, and does not create undue burden on the mother.
    subject.
  • 5.4.2.2. If PI wishes to list specific forms of birth control in any of the above categories (rather than the generic “appropriateeffective method(s) of birth control” found in the IRB-approved template), and use of an effective form of contraception is allowed per section 4.0, then the list must include at least (1) condoms (malebarrier or female)double barrier methods with or without a spermicidal agentagent.
  and
  (2) diaphragm or cervical cap with spermicide, unless the sponsor/PI presents justification that any of these are medically or scientifically inappropriate considering both the nature of the research and the subject population.
• 5.5.3. The IRB Executive Chair, on behalf of the IRB Executive Committee,Chair is authorized to negotiate with sponsors and/or PIs to address requests for specific language modifications in the ICF provided the requested modifications are at least as protective as the requirements found in the IRB-approved template.
• 5.4. In the case of minors and those with impaired decision-making capacity, risks to those who can become pregnant or contribute to a pregnancy, as well as contraception requirements, will be discussed in a developmentally and cognitively appropriate manner.