Relative Bioavailability and Food Effect of Asciminib Pediatric Mini‐tablet Formulation Compared to the Reference Tablet Formulation in Healthy Adult Participants

Asciminib, a first‐in‐class allosteric BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP) is used in the treatment of chronic myeloid leukemia. We describe a randomized, single‐dose, open‐label, four‐period crossover study in healthy adult participants (N = 24) which evaluated the relative bioavailability of a single 40‐mg dose of asciminib in pediatric formulation (1‐mg mini‐tablets) compared with the reference adult tablet under fasted conditions. Additionally, the effect of food on the bioavailability of the mini‐tablet formulation was evaluated. Under fasted conditions, asciminib exposure was similar for both formulations (geometric mean [Gmean] area under the concentration–time curve from time 0 to infinity [AUCinf] 5970 and 5700 ng ×h/mL, respectively). Food decreased the AUCinf and maximum plasma concentration (Cmax) of the asciminib mini‐tablets; this effect was more pronounced with a high‐fat meal (Gmean ratios [90% confidence interval]: fasted/low‐fat meal, 0.42 [0.38–047], 0.32 [0.28–0.37], respectively; fasted/high‐fat meal, 0.30 [0.27–0.34], 0.22 [0.19–0.25], respectively). The mini‐tablets were assessed to be easy to ingest with good palatability. Asciminib doses for a pivotal pediatric clinical trial will be defined using physiologically based pharmacokinetic modeling, which will consider the age and the higher food effect observed with the mini‐tablets.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from the clonal proliferation of transformed hematopoietic progenitor cells. 1 CML can occur at any age but is most common in adults aged over 65 with a median age at diagnosis of 57-66 years. 2 CML rarely occurs in the first few decades of life, accounting for 2%-3% of leukemias in children <15 years and 9% in adolescents aged 15-19 years. 3 Children <15 years have an annual incidence of CML ranging from 0.6 to 1.0 cases per million and adolescents aged 15-19 years have an annual incidence of 2.1 cases per million. 3 Tyrosine kinase inhibitors (TKIs) that target BCR::ABL1 are the standard of care for adult and pediatric patients with CML in the chronic phase (CML-CP). Asciminib is a first-in-class orally administered agent that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP), potently inhibiting the kinase activity of ABL1, ABL2, and the chimeric oncoprotein BCR::ABL1 via allosteric binding. [4][5][6] Studies in patients with CML and healthy volunteers revealed that peak blood concentration and exposure of asciminib are roughly dose-proportional, with a half-life of 14.2 hours and a time to maximum plasma concentration (t max ) of 2 hours after administration. 7,8 Human disposition studies indicated that asciminib is mainly cleared by hepatic metabolism and eliminated via biliary secretion involving three pathways: oxidation by cytochrome P450 (CYP3A), glucuronidation by uridine-5-diphospho-glucuronosyltransferase enzymes in the liver, and biliary secretion by breast cancer resistance protein efflux transporters; each pathway contributes roughly one-third to the overall clearance. 8,9 Asciminib has been shown to be weakly affected by concomitant use with CYP3A inducers, CYP3A4 inhibitors, or inhibitors of P-glycoprotein. 10 A food effect analysis showed that administration of asciminib with food reduced exposure, the effect of which was more pronounced with higher dietary fat content. 11 Similarly, administration of asciminib with food compared with fasted conditions delayed t max and the change in t max increased with dietary fat content. 11 Asciminib was evaluated in the pivotal phase III randomized controlled trial, ASCEMBL (NCT03106779), in which asciminib 40 mg twice daily (BID) demonstrated superior efficacy and improved safety and tolerability versus bosutinib 500 mg once daily in adult patients with CML-CP who had been treated with ≥2 prior adenosine triphosphate (ATP)-competitive TKIs. 12 For adult patients, asciminib 20-and 40mg film-coated tablets have been developed. However, due to size (6.2-and 8.2-mm diameter, respectively), these tablets will be unsuitable for oral administration in younger pediatric patients. Furthermore, the adult dosage strengths do not allow for a sufficiently flexible and accurate pediatric dosing which will be individualized based on body weight. To cover the anticipated pediatric dose range and provide an appropriate formulation for younger patients, asciminib 1-mg film-coated mini-tablets (with a diameter of 2 mm), have been developed and are considered a suitable dosage form for adolescents and children aged 2-11 years.
The aim of this study was to assess the relative bioavailability of the newly developed pediatric formulation of asciminib (1-mg mini-tablets) compared with the reference adult tablet formulation (40-mg tablet) following a single oral administration of 40 mg of asciminib of each formulation in healthy adult participants under fasted conditions. Additionally, the effect of food on the bioavailability of the mini-tablet formulation when administered with a low-fat or high-fat meal was evaluated. The acceptability and palatability of the mini-tablets were also assessed by a questionnaire. Based on these data, the initial starting dose of asciminib mini-tablets in the pivotal pediatric study under fed conditions (ASC4KIDS; NCT04925479) 13 will be defined using physiologically based pharmacokinetic (PBPK) modeling.

Study Design
This was a randomized, single-dose, open-label, fourperiod crossover study in healthy adult volunteers (Figure S1). Participants were enrolled and randomized to receive asciminib in one of four possible treatment sequences in a 1:1:1:1 ratio according to the Williams square design. In each treatment period, asciminib (as hydrochloride salt), was administered on days 1, 6, 11, and 16 as a single 40-mg tablet under fasted conditions or as 40 1-mg mini-tablets under fasted conditions, fed with a low-fat meal or fed with a high-fat meal. Following each asciminib dose, there was a 5-day washout period (beginning immediately after dosing). The total duration of the study treatment was 20 days with an additional screening period of a maximum of 21 days and a safety follow-up of 30 days after the last dose ( Figure S1).
The mini-tablets were supplied as size 0 capsules (primary packaging not intended to be swallowed) containing 20 mini-tablets. Asciminib was administered in the morning after an overnight fast of ≥10 hours with approximately 240 mL of water, either under fasted conditions (ie, no breakfast) or 30 minutes after the start of a low-fat or high-fat breakfast. Participants were required to fast for ≥4 hours after study treatment administration. The composition of the low-fat and high-fat meals was based on guidance from the US Food and Drug Administration 14 ; the high-fat meal consisted of 800-1000 calories (of which ≈50% of calories were from fat, ≈35% carbohydrate, and ≈15% protein, eg, two fried eggs, two strips of bacon, two slices of toast with butter, 4 oz of hash brown potatoes, and 8 oz of milk) and the low-fat meal consisted of 400-500 calories (of which ≈25% of calories were from fat, eg, 8 oz of milk, one boiled egg, and one packet of flavored instant oatmeal made with water). Participants were required to consume the entire meal provided; any event of incomplete meal consumption was recorded. Intake of fluids was prohibited from 1 hour before dosing until 1 hour after, except for fluid taken with breakfast before dosing and water for study drug intake. Otherwise, water was permitted.
At any time, participants could withdraw from the study for any reason. In the case of adverse events (AEs) that required participant withdrawal, or aberrant laboratory or clinical assessments, investigators were to stop study treatment. No dose modifications or breaks were allowed. Until the end of treatment, no concomitant medications could be taken, other than those needed to treat AEs.
The study was performed in accordance with the Declaration of Helsinki and the International Conference on Harmonization Harmonized Tripartite Guidelines for Good Clinical Practice. All participants gave written informed consent before participating and before any study-specific procedures were initiated. This study was carried out by Parexel International GmbH, Early Phase Clinical Unit, Berlin, Germany on behalf of the study sponsor Novartis Pharmaceuticals Corporation. The protocol was reviewed and approved by the German Health Authority and the local ethics committee (Landesamt für Gesundheit und Soziales, Ethik-Kommission des Landes Berlin, Turmstrasse 21, 10559 Berlin).

Study Objectives
The objective of this study was to assess the relative bioavailability of the pediatric formulation of asciminib (1 mg mini-tablets) compared with the reference adult formulation (40 mg tablet) following single oral administration of 40 mg of asciminib of each formulation in healthy adult participants under fasted conditions. Additionally, this study aimed to assess the effect of food on the bioavailability of the mini-tablet formulation under low-fat and high-fat conditions compared to fasted conditions. The acceptability and palatability of the mini-tablets, as assessed by a specific questionnaire, was an exploratory endpoint.

Study Participants
Participants in this study were adult (18-55 years old) men and/or women not of childbearing potential, with a body mass index between 18.0 and 29.9 kg/m2. Participants were deemed to be healthy at enrollment (based on their medical history and the results of their physical examination, vital signs, electrocardiogram [ECG], and clinical laboratory testing at screening). Due to data on the teratogenicity of asciminib in animal studies, women of childbearing potential were excluded from this study. Other key exclusion criteria included history or presence of cardiac abnormalities (including cardiac repolarization abnormalities), a history or presence of immunodeficiencies, any surgical or medical conditions that could interfere with the absorption, distribution, metabolism, or excretion of asciminib, a history of malignancy in any organ system (with the exception of localized basal cell carcinoma of the skin or in situ cervical cancer), a history of acute pancreatitis, chronic pancreatitis or any ongoing pancreatic disease, and smoking.

Assessments
Pharmacokinetic (PK) parameters included the area under the plasma concentration-time curve (AUC) from time 0 to the time of last measurable concentration (AUC last ), AUC from time 0 to infinity (AUC inf ), maximum observed plasma concentration after drug administration (C max ), t max , the elimination half-life associated with the terminal slope of a semilogarithmic concentration-time curve (t 1/2 ), and the apparent total body clearance of drug from the plasma (CL/F).
For the assessment of asciminib PK, serial blood samples were collected prior to administration (0 hours) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours following administration. Plasma concentrations of asciminib were measured as previously described using a validated liquid chromatographytandem mass spectrometry assay with a lower limit of quantification (LLOQ) of 1.0 ng/mL. 11 To assess the acceptability and palatability, participants completed a questionnaire in which they were asked to rate (very good, good, neither good nor bad, bad, or very bad) the treatments based on the ease of ingesting the tablets, after-taste, smell, and feel in the mouth of the asciminib reference tablet and mini-tablets. The questionnaire was completed within 15 minutes of each drug administration.
The safety of asciminib was assessed via hematology, blood chemistry, urine analysis, ECG, monitoring of vital signs and physical condition, and AEs. AEs were coded using MedDRA version 24.0 and graded according to Common Terminology Criteria for Adverse Events version 5.0.

Statistical Analysis
The full analysis set included all participants to whom a treatment sequence was assigned and was used to summarize baseline characteristics and demographics; the safety set included all participants who received any study drug and was used for all safety analyses. The PK analysis set included all participants who provided at least 1 evaluable PK profile and was used for all the PK data analyses. A PK profile was considered evaluable if the participant had received the planned dose of asciminib, provided at least 1 primary PK parameter, had predose concentrations ≤5% of C max , fulfilled the specified fasting requirements prior to and following dosing, consumed at least 75% of the meal for the fed treatments, and had not vomited within 4 hours after intake of asciminib.
Baseline characteristics were presented as frequencies and percentages for categorical data and median, minimum, and maximum for continuous data. PK parameters were calculated from the individual concentration-time profiles by a noncompartmental method using Phoenix WinNonlin (Pharsight, Mountain View, California) software version 8.0. Descriptive statistics (mean, standard deviation, geometric mean [G mean ], and geometric coefficients of variation [GCV%]) were calculated for all PK parameters except for t max, for which only the median and range were determined. A linear mixed-effects model was fitted to the log-transformed PK parameters (AUC last , AUC inf , and C max ). The model included treatment, period, and sequence as fixed factors and participants nested within the sequence as a random factor. To evaluate the relative bioavailability of a pediatric mini-tablet formulation of asciminib (under fed and fasted Mean asciminib concentration (ng/mL) 01234  conditions) compared to the reference tablet formulation (under fasted conditions), a point estimate and the corresponding 90% confidence interval (CI) for the difference between least-square means of the mini-tablets (test) and reference tablets (test-reference) were calculated. These were back-transformed to obtain the point estimate and the 90%CI for the ratio of the G mean on the untransformed scale. For t max , median and range of difference between test and reference treatment were provided. Individual participant ratios (test:reference) and G mean ratios (90%CI) for asciminib plasma PK parameters were plotted. All drug concentrations below the LLOQ were set to 0 and treated as missing for the calculation of G mean and GCV%. Participants with missing PK parameters in some but not all periods were included in a mixed-model analysis assuming missing at random.
All analyses were performed using Statistical Analysis System (SAS) version 9.4.
Using an assumed intraparticipant CV of 29% (based on the largest GCV% of AUC inf , AUC last , and C max from previous asciminib PK studies 11,15 ) and a sample size of 18, the precision or half-width of the 90%CI for test-reference comparison on the log scale was extended 0.1648 from the observed difference in means. This calculation was based on a paired t-test with two-sided alpha level of 10% and 17°of freedom. Considering a dropout rate of 15%, 24 participants (six per treatment sequence) were enrolled to obtain approximately 18 evaluable participants.

Participant Disposition and Baseline Characteristics
A total of 24 participants were enrolled and randomized in the study, of whom 23 completed the study per protocol; 1 participant discontinued due to an AE after study enrollment but before the first planned administration of the study drug and hence was not treated and was therefore excluded from the PK analysis. Most of the participants were Caucasian (20/24) and predominantly male (22/24), with a median age of 46 years (range 20-55) (Table S1).

PK Analyses
The final PK analysis set included 23 participants. Under fasted conditions, the arithmetic mean concentration-time profiles revealed comparable rate and extent of absorption of asciminib when administered as a single 40-mg tablet or as 40 1-mg mini-tablets (Figure 1). According to the arithmetic mean concentration-time profiles of the asciminib mini-tablets under different food conditions, there was a negative effect of food on the absorption of the mini-tablets, with lower exposure and delayed t max with increased meal fat content in comparison to fasted conditions (Figure 1).
In the fasted state, similar exposure (AUC inf , AUC last , and C max ) was observed for the asciminib reference tablet and the mini-tablets (Table 1). When the mini-tablets were administered with a low-fat or high-fat meal compared to fasted conditions, a greater decrease in asciminib exposure was observed with a high-fat meal compared with a low-fat meal (Table 1). A statistical comparison of asciminib PK parameters confirmed these observations, revealing that the higher the fat content of the meal, the lower the exposure to asciminib (Table 2). Under fasted conditions, all G mean ratios and 90%CIs were within the standard bioequivalence range of 80.00%-125.00%, demonstrating that asciminib exposure for the mini-tablet formulation was similar to the reference tablet formulation. Exposure to asciminib was lower when the minitablets were administered with a high-or low-fat meal compared with fasted conditions. Under low-fat meal conditions, the G mean ratios for AUC inf and AUC last indicated a 58% decrease in exposure compared to fasted conditions. Likewise, the G mean ratio for C max indicated a 68% decrease after a low-fat meal compared to fasted conditions. A greater decrease in asciminib exposure was observed with an accompanying high-fat meal, with the G mean ratios for AUC inf and AUC last indicating an approximate 70% decrease in exposure compared to fasted conditions. The G mean ratio for C max indicated a 78% decrease in C max after a high-fat meal as compared to fasted conditions. Under both low-fat and high-fat fed conditions, the median t max of the asciminib mini-tablets was prolonged to 5.0 hours compared with 2.0 hours under fasted conditions. The G mean t 1/2 was similar irrespective of formulation or meal conditions (approximately 13 hours). Under fasted conditions, the G mean clearance was similar for the asciminib reference tablet and mini-tablets (CL/F: 6.70 and 7.01 L/h, respectively), which increased under fed conditions (CL/F: low-fat meal 16.6 L/h, high-fat meal 23.2 L/h). The interparticipant variability for PK parameters was higher when asciminib mini-tablets were administered with a high-fat meal (GCV% AUC inf 41.8%, AUC last 42.6%, C max 47.3%) or a low-fat meal (GCV% AUC inf 38.4%, AUC last 38.0%, C max 44.4%) compared with fasted conditions (GCV% AUC inf 21.3%, AUC last 21.2%, C max 27.3%).

Palatability and Acceptability
Most participants (82.6%) indicated that ingesting the asciminib reference tablets was very easy. Neutral responses (neither good nor bad) were received from 65.2% and 69.6% of participants for the taste/aftertaste and the smell of the reference tablets, respectively; 43.5% of participants said the feel in the mouth of the reference tablet was neither good nor bad. For the asciminib mini-tablets, across the three meal conditions, most participants (60.9%-69.6%) rated the ease of ingesting the references tables as very easy. The majority of participants rated the taste/aftertaste (65.2%-69.6%) and the smell (56.5%-69.6%) of the mini-tablets as neither good nor bad. The feel in the mouth of the minitablets was reported as neither good nor bad by 43.5%-56.5% of participants. For both formulations, no participants reported any difficulty in taking the tablets or a very bad or bad taste, smell or feel in the mouth.

Safety
At least 1 AE was reported in six participants (26.1%) ( Table 3). The most frequently reported AEs were gastrointestinal disorders (three participants, 13.0%), The model is a linear mixed-effects model fitted to the log-transformed PK parameters (AUC last , AUC inf , and C max ). Included in the model were treatment, period, and sequence as fixed factors and participants nested within sequences as a random factor. Results were back-transformed to calculate the adjusted G mean , G mean ratio, and 90%CI. The PK parameter t max was included in this statistical analysis for comparison of treatments. For t max , median is presented under "Adjusted G mean, " median difference under "G mean ratio," and range under "90%CI." AUC, area under the plasma concentration-time curve; AUC inf , AUC from time 0 to infinity; AUC last , AUC from time 0 to the time of last measurable concentration; CI, confidence interval; C max , maximum observed plasma concentration after drug administration; G mean , geometric mean; PK, pharmacokinetic; t max , time to reach maximum plasma drug concentration. a Median difference. b Range.
with nausea being the most frequently reported AE (two participants, 8.7%). All other AEs were reported in 1 participant each. Of the six participants with at least 1 AE, three participants reported four AEs, which were suspected to be study drug-related and included nausea, amylase increase, and dysgeusia (reported in 1 participant each). All AEs were grade 1 (n = 4) or 2 (n = 2) and there were no serious AEs or deaths. The two grade 2 AEs were amylase increase and COVID-19, reported in 1 participant each. The participant with an AE of amylase increase showed a transient increase of 5× the upper limit of normal (ULN) on day 4 (treat-ment period 1) which remained elevated across all treatment periods and returned to normal ranges on the end of treatment visit; this event was reported as a grade 2 AE on days 4-7 (treatment periods 1 and 2) and grade 1 on days 9-19 (treatment periods 2, 3, and 4). The participant with grade 2 COVID-19 was diagnosed 13 days after the last dose of asciminib and recovered fully after 7 days (confirmed by a negative PCR test); this AE was not suspected to be study drug-related. One participant had elevated levels of triglycerides at baseline of treatment period 1 (screening) which remained elevated across all treatment periods and at the end of the treatment visit an increase of 3× ULN was observed; these abnormal laboratory values did not fulfil the criteria to be reported as AEs. There were no clinically significant abnormalities in vital signs or ECG.

Discussion
In this study the relative bioavailability of the pediatric formulation of asciminib (1-mg mini-tablets) compared to the reference asciminib tablet formulation was assessed in healthy adult participants under fasted conditions and the effect of food on the PK of the mini-tablets was established. In the fasted state, the PK exposure in terms of both AUC and C max of a single 40-mg dose of asciminib was similar when administered as the reference tablet or mini-tablets. Under fed conditions, a decrease in asciminib exposure was observed with the mini-tablets. Previous studies have shown the administration of asciminib with a low-fat and a high-fat meal to decrease bioavailability by approximately 30% and 60%, respectively, compared with fasted conditions. 11,15 Similar results were observed in the present study, although the magnitude of the food effect was more pronounced with the asciminib mini-tablets than with the asciminib reference tablet. Here, the effect of food was increased when the fat content of the meal was high, with the asciminib systemic exposure and C max decreasing by 58% and 68% with a low-fat meal and by 70% and 78% with a high-fat meal, respectively, compared with fasted conditions. The time to reach maximum plasma drug concentration (t max ) was 2 hours in the fasted state for both the asciminib reference and mini-tablets and was prolonged to 5 hours when the mini-tablets were administered with a low-fat or high-fat meal. The reason for the more pronounced food effect with the asciminib mini-tablets compared with the reference tablets is currently unknown. It has previously been hypothesized that asciminib is sequestered by bile acids secreted into the gut on food intake, which is thought to take the compound further down the lower gastrointestinal tract, where absorption may be limited. 11 In vitro dissolution tests with the mini-tablets showed no differences in the dissolution characteristics compared with the adult reference tablet, therefore a different food effect of the mini-tablets was unexpected (data not shown). Asciminib is a Biopharmaceutics Classification System (BCS) Class II compound (high permeability, low solubility) and the effect of food on asciminib is believed to be driven by sequestration to the bile salts, and hence is a manifestation of the physiochemical properties of asciminib unrelated to the BCS class. 11 As shown in the results reported here and previously, food has been found to affect the PK of asciminib. In adult patients with CML, asciminib 40 mg BID administered under fasted conditions has been evaluated in several clinical trials. 7,12 Given the mechanism of action of asciminib and the well-characterized molecular pathogenesis of CML, as well as disease characteristics, asciminib is anticipated to exhibit the same activity in adults and children. Thus, comparable efficacy of asciminib in children is expected if asciminib exposure is similar to the recommended adult dose. The proposed strategy for the development of asciminib for pediatric patients included the development of an age-appropriate dosage form, PK and food effect evaluation of the pediatric formulation, PBPK modeling to predict a pediatric asciminib starting dose matching adult exposure, and a PK study to establish pediatric asciminib dosing regimens. The findings from the present study will be used together with PBPK modeling of adult data to define the starting dose of asciminib for a pivotal pediatric study, which takes the metabolizing enzyme ontogeny (ie, differences in drug metabolism between children and adults) as well as the higher observed food effect and proposed administration with food into account. ASC4KIDS (NCT04925479) is a phase I/II trial, the objective of which is to characterize the PK profile of asciminib in pediatric patients with the goal of identifying a pediatric formulation dose (under fed conditions) comparable to the adult dose of 40 mg BID (under fasted conditions), which was shown to be safe and efficacious in adults. 13 The reference asciminib formulation is limited when considering the potential pediatric need for dose adjustment. A pediatric asciminib formulation in a form acceptable to all children that would allow for the dose to be adapted to varying body size and food conditions was sought. Due to known product degradation by hydrolysis, a liquid formulation of asciminib was not a feasible option, and hence asciminib 1-mg film-coated mini-tablets were developed. In pediatric patients, it is foreseen that asciminib will be administered twice daily and for convenience and treatment compliance a dosing regimen that can be taken with food is proposed. The mini-tablets are provided in a size 0 capsule as a dispensing aid; the capsule must not be swallowed, and the contents should be emptied directly into the patient's mouth or administered on a teaspoon. For pediatric patients unable to swallow the mini-tablets, administration with nonacidic liquid or soft food (eg, water, vanilla/chocolate milk/soya-based pudding, dairy/soy-based, or coconut milk) will be offered.
Asciminib has a slightly bitter taste. Using a similar approach to that established for other mini-tablets for pediatric indications, the asciminib mini-tablets are film-coated to mask the bitter taste. In healthy adult participants, both asciminib reference tablets and asciminib mini-tablets were well accepted with good palatability, confirming the successful taste masking. It is expected that the palatability would be similar in children. The acceptability questionnaire will also be used in the ASC4KIDS pediatric study and will therefore provide evidence for this population.
Single oral doses of asciminib (as 1 40-mg tablet or 40 1-mg mini-tablets) were well-tolerated and safe with and without food. AEs reported in the study were of low severity and resolved without sequelae. No deaths or serious AEs were reported in the study.
Amylase elevation was observed in 1 participant, although values returned to normal by the end of the study.
This study in healthy adult participants showed that the asciminib PK profile (exposure and concentration) was similar when administered either as 1 40-mg filmcoated tablet or as 40 1-mg mini-tablets in the fasted state. Administration of the mini-tablets led to a decrease in asciminib exposure which was more pronounced with a high-fat meal than with a low-fat meal. Both formulations of asciminib were well tolerated and accepted with good palatability in this healthy adult volunteer study. The information gained from this food effect study will be utilized in PBPK modeling to define the initial dose of asciminib (under fed conditions) in the pivotal pediatric clinical trial that would match the adult exposure under fasted conditions. contractual or consent provisions that prohibit transfer to third parties. Such restrictions may preclude granting access under these provisions. Where co-development agreements or other legal restrictions prevent companies from sharing particular data, companies will work with qualified requestors to provide summary information where possible.