TABLE OF CONTENTS
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1.0INTRODUCTory statement and general investigational plan......
1.1.Drug and Broad Objectives......
1.2.Previous Human Experience......
1.3.Drug Withdrawal from Investigation or Marketing......
1.4.Overall Investigational Plan......
2.0investigator’s brochure......
3.0Protocol......
4.0Chemistry, manufacturing, and control information......
4.1.Drug substance......
4.2.Drug product......
4.3.placebo......
4.4.Labeling......
4.5.Environmental analysis requirements......
5.0pharmacology and toxicology information......
6.0Previous human experience with the investigational drug......
7.0Other information......
7.1.Pediatric studies......
8.0REFERENCES......
NOTE: This example is for an indto study an approved drug in a new indication. information on cmc and toxicology would be considerably greater for an investigational product.INTRODUCTory statement and general investigational plan
1.1.Drug and Broad Objectives[l1]
[Product] is a [compound description], initially synthesized in [1969]. It is approved for clinical use as a [indication]. As a [mechanism of action], it exerts this effect in the [organ], but it also blocks [function] on the [cell type] surface. In [disease] there is a defect in [receptor] which is thought to secondarily lead to excessive [symptom] resulting in [disease characteristic]. This abnormal [observation] is measurable as [outcome measure]. It is known that systemic [Product] administration in human studies does not result in an effective concentration of [Product] at the [intended target organ], thus [route of administration] of the drug has been studied in [disease] in an effort to[mechanism of action] thereby potentially reducing the [clinical symptomology of interest].
Although most of the studies evaluating the role of [Product] in [disease] have focused on its use in [alternative usages], [Product] also has direct [mechanism of action] in vitro. It acts synergistically with [antibiotics] to augment antibacterial activity in vitro. Interestingly, this synergistic effect appears to be more pronounced against [bacterial species] than other common [organisms] such as [bacteria]and [bacteria]. This may explain prior mixed results in clinical efficacy trials involving patients colonized with [bacteria]. A recent case report demonstrated eradication of [bacteria] from the airways of 3 out of 4 patients with [disease] after 6 months of treatment with a combination of aerosolized [Product] and [antibiotic].24 Eradication of [bacteria] would be expected to be associated with significant clinical benefit, including a reduction in pulmonary exacerbations, amelioration of the rate of decline in lung function, and a significant improvement in mortality.
The broad objective of this investigation is to assess the safety and efficacy of treatment with [Product] solution for inhalation and [antibiotic]in patients with [bacterial] respiratory tract infections. The planned duration of the investigation is two years.
1.2.Previous Human Experience[l2]
[Product] solution for inhalation has been studied in Australia and under IND XX,XXX in the United States. Please see section 2.4 of the protocol (Appendix 2) for additional information[l3]. A summary of the studies published in the literature are listed in Table 1. Please refer to IND XX,XXX for additional efficacy and safety data for the unpublished study XXXX.[l4]
Table 1. Listing of Relevant Literature[l5]
1.3.Drug Withdrawal from Investigation or Marketing
To our knowledge the drug has not been withdrawn from investigation or marketing for any reason related to safety or effectiveness. The bulk drug product, [Product], USP is being obtained from XXXX. This product is in powder form and will be formulated as a solution as indicated in Section XX.
1.4.Overall Investigational Plan
[Bacterial] infection is a particularly difficult problem to treat in [disease] because of intrinsic antibiotic resistance. A number of patients at the [Hospital][City] have been infected with [bacteria], and an examination of clinical data from this population has demonstrated an increased decline in lung function and increased mortality. Our current clinical efforts to treat this infection are sorely disappointing. A recent case series from Australia demonstrated eradication of [bacteria] in 3 of 4 patients treated for up to six months with a combination of inhaled [Product] and inhaled [antibiotic].2 The proposed 6 month open-label trial is designed to determine the ability of [Product] solution for inhalation administered X times daily, and [antibiotic], administered twice daily, to eradicate [bacteria] respiratory tract infection in patients with [disease]. Secondary objectives include 1) evaluation of the safety and tolerability of multiple doses of [antibiotics], and 2) obtaining evidence of clinical efficacy of multiple doses of [antibiotics] as reflected in a change in [provide appropriate clinical measures]. We anticipate that up to XX patients will be enrolled in the trial. Particularly severe risks are not anticipated based on the prior investigational experience with this drug. This trial will be used to generate experience and data to support the design of a larger, multicenter trial investigating the efficacy of [antibiotics] in treating infection with other [bacterial] species in [disease].
2.0investigator’s brochure
An Investigator’s Brochure has not been prepared. Information related to the [Product]is provided in the form of the package insert for [Product], USP (Appendix X). Information on[ANTIBIOTIC] ™ is also provided in the form of a package insert (Appendix Y). Additional information regarding the inhaled formulation of [Product]is provided in the CMC and Nonclinical Sections of this application, as well as in the clinical protocol. Where appropriate, reference to IND XX,XXX is provided or [product] DMF.
3.0Protocol
Please see Appendix 2 for the complete clinical protocol for this pilot study. Curriculum vitae of the investigator and sub-investigators are included in Appendices 3-6. The research will be carried out at Children’s Hospital [address]. The Institutional Review Board of [institute], [address], will be responsible for the initial and continuing review and approval of the study.
4.0Chemistry, manufacturing, and control information[l6]
4.1.Drug substance
The drug substance used for preparation of [Product]is bulk [Product]. The chemical name is [Product]. [Product] is a yellow to greenish yellow, odorless or practically odorless crystalline compound, soluble in water. It is the salt of a moderately strong base, [Product], pKa 8.7. The drug substance is being purchased from [Company Name] (address). Refer to DMF # XXXXX for information regarding manufacture, packaging and labeling.
4.2.Drug product
[Drug Product] will be compounded by the [Hospital] pharmacy to a concentration of [XM]. Unopened, solid-state [Product], USP will be kept under their strict control during the duration of the study. Using aseptic techniques, Investigational Pharmacy personnel will dissolve X mg of [Product] USP into X mL of preservative free sterile water (USP). To this solution, X mL of sterile, preservative free normal saline (0.225% NaCl) will be added to achieve a final osmolarity of X. As a final step, the pH of the solution will be adjusted to 4.0 with 1N HCl (USP). The solution will then be filtered through a 0.22 um membrane filter into sterile glass vials (wrapped for light protection), each to contain X mg [Product]in Y mL, a Z mM solution. Three aliquots will be randomly selected for sterility testing prior to drug distribution. The drug will be stored at room temperature, protected from light, and will be labeled with an expiration date 12 weeks from the date of solution preparation. Refer to IND XX,XXX for information on the stability of vialed solutions.
4.3.Placebo
No placebo is being used in this trial.
4.4.Labeling
The labels for the [drug product ]will include the following: “Store Between 15°C and 25°C”, “Keep Out of Reach of Children”, “For Clinical Trial Use Only”, "Caution: New Drug: Limited by Federal (USA) Law to Investigational Use Only".
4.5.Environmental analysis requirements
We are claiming a categorical exclusion under 21 CFR 25.31 (e).
5.0pharmacology and toxicology information[l7]
Animal Studies. Studies of [Product] have been conducted in dogs and sheep (ref). In anesthetized dogs given nebulized [Product], XmL of a Y mM solution was found to result in peak [Product] concentrations in airway surface fluid of X M in the trachea and Y M in the large bronchi, immediately after nebulization. Administration of X mM [Product] to sheep via nebulization over 5 minutes resulted in a measured airway surface fluid concentration of [Product] of YM. At 30 minutes the concentration was X M and by 60 minutes it was less than Y M. The calculated half-life in the airway was X minutes. Aerosolization was well tolerated in the dog, resulting in no significant change in plasma pH, PaO2, PaCO2, mean aortic pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, heart rate, diffusing capacity of carbon monoxide, functional residual capacity, airway compliance, and oxygen consumption. There was also no change in serum electrolyte concentration 1 hr after [Product] administration.
6.0Previous human experience with the investigational drug[l8]
A number of studies have already been conducted with [DRUG PRODUCT]and reported in the clinical literature. These studies are summarized in Tables 1 and 2. Table 2 tabulates the dosing information from each of those studies.
Pharmacokinetics. Normal human subjects given Y mL of a Z mM solution via nebulization were found to have a calculated maximal airway surface fluid concentration of [Product] of X M and an airway surface fluid half life of approximately X minutes and first order kinetics. Plasma concentrations increased rapidly after nebulization to a peak of X ng/mL at 30 minutes, suggesting most of the drug is absorbed systemically from the airway. Excretion of X% of the absorbed [Product] was noted in urine in the first 24 hours, and none was detected in the urine by 48 hours. Patients administered a similar dose orally had no detectable blood level at 30 minutes, suggesting the early peak was secondary to absorption via the airway as opposed to a swallowed portion of the nebulized drug.26
Safety Information. [Product] was well tolerated in normal subjects and subjects with [disease] both acutely and in studies with treatment periods of up to 6 months. It has been administered safely to patients with [disease] in a number of dosages as summarized in Table 2.In the summarized studies, researchers examined varying combinations of the following parameters and found no adverse effect compared to baseline or placebo control treatment arm in blood pressure, lung function (IVC, FVC, FEV1, PEFR), oxygen saturation, body weight, serum urea, serum electrolyte concentration, number of oral or IV antibiotic courses, bacterial sputum densities [bacteria) or sputum volume.
In one trial, X patients (total n=200) did not complete the study, often due to protocol violations or personal reasons. However, X of the Y patients were assessed to have stopped due to an adverse event. One 18-year-old patient developed [clinical observation]. Two patients were diagnosed with [secondary condition], one of whom had a history of [symptom] which predated the study. A fourth patient developed [symptom] that was not further described. Other possible adverse events identified in this trial are not itemized in the study, and were not considered significant. Similar adverse events were not seen in other trials, though other trials involved fewer patients.
Efficacy Information. [Authors] studied the in vivo antimicrobial effect of [Product] for up to 6 months in 4 patients colonized with [bacteria].Eradication of the bacteria from the airways was noted in 3 of the 4 patients studied, and this eradication persisted for at least 2 years. This is remarkable because it is quite rare for [bacteria] to be eliminated from the airway in [disease]. It is estimated that colonization with [bacteria]is transient in approximately 6% of cases. This estimate is based on a definition of colonization as only 1 positive airway culture. [Author] group defined baseline colonization as more than 3 positive cultures, thus it might be expected that their rates of spontaneous resolution would be even lower, making the report of eradication in 3 out of 4 patients even more dramatic. All isolates in the [Author] study were [antibiotic] resistant, which lends credence to the in vitro synergy data noted above.
Table 1. Summary of Other Clinical Investigations with [Product]
Study Number / Name of Study / Patients[l9] / Highest Dose / Duration of Dosing / Reference7.0Other information
7.1.Pediatric studies[l10]
Pediatric patients 6 years and older are eligible for the trial.
8.0REFERENCES
Comprehensive List of all References. Copies can be provided, particularly if not easily obtained.
EXAMPLE IND – NEW INDICATIONJune 26, 20091
[l1]This section should contain information about the clinical indication and the reasons that you think the product has a place in the treatment of these patients.
[l2]This section contains any known information from literature, abstracts, or previous experience.
[l3]In addition to the information in the protocol, I advise summarizing the essential components of each study in a table so that the FDA can better see what the clinical experience has been to date.
[l4]If there is any unpublished data provided in the IND that you want considered, please refer to it here.
[l5]This is a suggestion to help guide the FDA reviewer to the right papers.
[l6]For an approved entity, this section can refer to the label or if the innovator company is willing, reference the original IND.
[l7]This section should include any relevant animal or in vitro data that supports the use of the product in the new indication.
[l8]This section should include any information related to the PK and or safety that are relevant to the proposed studies. Any information related to safety is particularly important – and should be reflected in the tests to be conducted during the proposed clinical study.
[l9]This could include diagnosis, age, infection status
[l10]If you are proposing a different age group than is currently indicated in the product label, justification should be provided here.