ParameterMinimally AcceptableOptimally PreferredAnnotations IndicationPre-Exposure Prophylaxis with long-acting injectables to protect against HIV infection Drug class and common useMay be used for HIV treatment, but not as a first line drug Not used for HIV treatment Target PopulationKey population at risk of HIV infection e.g. MSM, adolescent girls and boys, sex workers, IDUs, transgender persons, pregnant women. Any person at high risk for HIV infectionBased on adequate clinical safety data in global populations targeted for commercialization and product introduction and use Safety & TolerabilityThe minimally acceptable general safety profile should be equivalent to currently approved PrEP agents. >90% of potential users adapt to tolerability and injection site issues within 1 round of use No damage to mucosal compartments relevant to HIV acquisition; no systemic toxicity; no significant induction of inflammatory response markers. No significant safety findings or findings that would suggest increased risk with use for >1 year. No significant barriers to long term tolerability, i.e. Adaption phase less than 1 month. Injection site discomfort less than 3 days LA Injectable products cannot be removed once administered, therefore safety must be well characterized. Importantly, the need for oral run in dosing with the ARV API must be determined and if needed, appropriately evaluated Dosing & AdministrationIntramuscular or subcutaneous injection by a health professional or community health worker with no more than two, 1 mL injections administered at bimonthly intervals A single injection with no more than 0.5 mL in volume administered at >3 month intervals The dosing volume and interval will need to have well demonstrated acceptability in the target population, Injection Site Reactions (ISR) will likely be the most common AE, and therefore must occur at an acceptable frequency and intensity. The possibility of self injection might also be explored Ideal properties for HIV Long Acting Injectables for HIV Prevention

ParameterMinimally AcceptableOptimally PreferredAnnotations FormulationsFormulation requires processing prior to injection, i.e. mixing, resuspension of dry powder and must be administered by a health professional or community health worker Formulation requires no processing prior to injection. Aqueous formulation that may be delivered via a pre-filled device Based on currently available commercial long acting parenteral formulations or vaccines used in target populations. Administered by health care professionals or community health worker with appropriate training. Unacceptable formulations will be those that would require freezing or refrigeration Product UseSame as optimalDemonstrated likelihood of uptake and sustained use of the product by women of diverse race, age, and geographic location as assessed by behavioral and perceptibility studies Monitoring post trialEvery 3 months6months/one yearThis refers to HIV and safety parameters relevant to a specific drug/product. More frequent testing might be required during evaluation in clinical trials Efficacy Efficacy will be determined by Phase III studies. Estimates of efficacy to be used as Go/ No-go for development purposes may be derived from PK/PD studies in in vitro and in vivo models. PK estimates for blood and tissues should meet best estimated Fold above Treatment IC90/95 if a treatment ARV. For non-treatment ARVs >90 % protection in an appropriate animal model PharmacologyRequires 1 month or less Oral or other route lead in to establish steady state levels at mucosal sites of infection. Single administration duration of no less than 2 months with a window of forgiveness of 30 days defined by the PK of the compound. Demonstrated penetration in the tissue compartments of effect Rapidly achievable therapeutic levels and steady state concentrations achieved within 1 week of administration at mucosal sites of infection with no lead in dosing. Single injection effect duration of no less than 3 months with a window of forgiveness of at least 30 days (no toxicity if given <30 days early and no drug resistance or protection failure if given <30 days late). Achievement of below level of detection of the drug in tissue/blood in no more than 60 days Determining the effective concentration will require appropriate safety and efficacy studies in relevant models involving dose escalation assessments. Once the safe and effective target exposure is defined, it will be necessary to determine the appropriate drug load/dose

ParameterMinimally AcceptableOptimally PreferredAnnotations ResistanceSame as optimalHigh genetic barrier to development of resistance, with any cross-resistance mutations to drugs in the same class having minimal impact on use of same class for treatment Analysis of resistance variants may need to factor in the effect of the mutations on viral fitness and fold-loss of inhibition versus other inhibitors in a class ContraindicationsSame as optimalNo food limitations. No contraindication for pregnancy, breast feeding or use of contraceptives and common medications (prescription and OTC) Possible ARV contraindications are likely to be drug type specific and should be known from treatment indications if a currently used ARV. Of particular interest are interactions with contraceptives, TB drugs, and drugs for common use therapies within target populations Cold chain, shelf life, storage, packagingShelf Life: Minimum 36 months; Storage conditions: minimum 30 o C, 65% RH, may require light blocking over-wrap and more than minimal packaging and manipulation to release the dose form Shelf life: 60 months; no restrictions on storage conditions: no cold chain; light stable, easy access Temperature cycling, freeze thaw and appropriate excursion studies will be required Cost of goodsComparable to or less than ARVS in developed country Comparable to contraceptives and other preventive interventions for other infections The cost of producing the drug product must be acceptable to procurement organizations, and be justifiable relative to claimed public health impact in the context of other prevention options Manufacturing/Supply chainRequires Procurement organization/ use region (country) investment in scale-up of manufacturing capacity and/or development of adequate supplies of precursor reagents Manufactured at scale with existing infrastructure and precursor reagents. Minimal investment to implement the supply and delivery chain