FDA Notes

Pre-IND

June 11, 1999

Lance L. Gooberman, M.D.
One South Centre Street, Suite 301
Merchantville, New Jersey 08109

Dear Dr. Gooberman:

Please refer to the pre-IND meeting between representatives of your firm and FDA on May 26, 1999. The purpose of the meeting was to further explore the toxicological and clinical study requirements for marketing approval of your product, depo-naltrexone to block the pharmacological effects of exogenously administered opioids.

As requested, a copy of our minutes of that meeting is enclosed. These minutes are the official minutes of the meeting. Please notify us of any significant differences in understanding you may have regarding the meeting outcomes.

If you have any questions, please contact Tony Chite, P.D., Regulatory Project Manager, at (301) 827-7410.

Sincerely,

Corinne P. Moody

Enclosure

Pre-IND Meeting

Page 2

Mr. Sasinowski began the presentation stating that Dr. Gooberman and his colleagues have taken into consideration the comments provided by the division in our letter, and have decided to abandon the pharmacokinetics-based development strategy. Instead, they plan to conduct an efficacy study and a safety study, with the help of Dr. O’Brien. Dr. DiGregorio will help address the pharm/tox issues raised in the letter. Dr. Gooberman is aware that current law allows him to compound this product for his own patients, but demand from his colleagues and his own conviction that the drug represents a public health benefit have lead him to pursue commercial distribution of the drug through the NDA process. He hopes, after initial studies are complete, to interest a commercial sponsor in bringing the product to market. However, at this point he is financing the development plan himself.

Mr. Sasinowski summarized the clinical experience and pilot data collected by Dr. Gooberman on his product since 1996.

Dr. O’Brien acknowledged a need for an efficacy study, saying that the relationship between blood levels of naltrexone and opiate blockade effect was tenuous, and because of the strong affinity of the drug for the μ -receptor, the blockade may actually outlast the blood level. He described the proposed efficacy study, the primary purpose of which would be to characterize the duration of the opiate blockade produced by the pellet. Thirty recently detoxified drug-free former opiate addicts would receive the depo- naltrexone pellet and be challenged with 8 mg hydromorphone at 24 hours, 48 hours, 1 week, and then weekly until breakthrough of drug effect is noted. PK samples would be obtained at each visit. The primary measure of blockade would be pupillometry, chosen because it is objective and not subject to misrepresentation by patients. VAS measurements of high and rush would also be obtained as secondary measures. Patients would be followed as outpatients, and urine drug screen for opiates would be obtained as additional secondary measures of efficacy.

Dr. O’Brien then briefly described a proposed safety study, which would involve 300 patients, 100 of whom would receive repeated implants. Safety parameters would be blood chemistries and implantation site toxicity at baseline, 1 month and 2 months.

In the proposed preclinical study there would be full size pellet implantation for 60 days. There would be injection site monitoring. The recovery phase would be 30 days. The anticipated problems concerned the liver and the site where the pellet was implanted.

The Agency stated that the overview of that which was presented was good, but more substantial information was needed on this framework. The Agency would like to give the groundwork for what the sponsor needs to overcome. The sponsor prefers to have the perspective of what needs to be done and the cost involved, since most of the resources to fund this project are solely the sponsor’s.

Pre-IND Meeting

Page 3

By discipline, the sponsor was informed of what additional information was needed.

The sponsor was briefed on the process and requirements for chemistry manufacturing and controls. An elementary description of the drug substance and the drug product was described. For the IND, Dr. Gooberman was told that the following would be required:

• Upon acceptance of the drug substance, a test should be done to establish the identity of the active ingredients. In this case, it was the naltrexone and the triamcinolone acetonide.
• An assay should be done on the finished drug product.
• The packaging for the drug should be described.
• The sterilization process, gamma irradiation, and the results of the U.S.P. sterility test for the fully packaged product should be provided.
• A limited amount of stability data should be provided to show that the material is unchanged for the duration of the clinical trials.
• Dr. Gooberman was told that the process description as provided in the pre-IND material was sufficient.

• A GLP bridging study will be needed.
• Protocol and details, including control group, needed for review with GLP study.
• Appropriate species would have the same ADME (metabolic profile) to humans.
• Batch numbers are required.
• Formulation used for the animal bridging study should be the same as the one to be used clinically (i.e., 1000 mg naltrexone pellet).
• Reproductive toxicology, carcinogenicity, and mutagenicity data are needed for package insert.
• Implantation site examination should include histopathology.
• Study in guinea pig model needed for hypersensitization concern.
• TK in recovery group should include several time points.

For the initial IND submission, no new data is needed. However, the sponsor is encouraged to develop an in vitro dissolution release testing methodology for this product as soon as possible. Final dissolution release specifications will be set, based on dissolution release data obtained from the batch used in the pharmacokinetic study.

Pre-IND Meeting

Page 4

CLINICAL:

• The pharmacologic effect of long-term blockade of exogenous opioids is not viewed as a clinically meaningful claim. It may be acceptable to view demonstration of this effect as a surrogate, suitable for initial approval and requiring Phase IV validation in clinical trials.
• It may be possible to modify the proposed efficacy study to focus on clinical endpoints. Alternatively, it may be appropriate to study the pharmacologic effect (extent and duration of opiate blockade) separately, perhaps in normal volunteers or non-treatment-seeking non-dependent opiate abusers. A separate trial of the effect of the drug on relapse to opiate use could then be designed for optimal collection of clinical endpoints.
• The clinical efficacy study should be controlled. Either a comparison to oral naltrexone or dose-controlled study would be appropriate. Dose-control designs are also attractive for identifying the minimum effective dose.
• Complete characterization of the pharmacokinetics of the drug, particularly early after administration is necessary.
• The proposed safety study should be larger and should expose at least 100 patients for longer duration (6 months to a year). ICH guidelines on the extent of exposure for a new molecular entity call for 100-1500 patients, with 300 exposed for 6 months and 100 exposed for a year. Naltrexone is not an NME, and there is information on the safety of the oral product, but this is a new formulation and exposes patients to sustained, rather than intermittent, blood levels. The AUC may be higher than the oral product even if the Cmax is lower. Therefore, although extent of exposure can be less than the ICH recommendation, 300 total patients is unlikely to be sufficient to characterize the safety.
• Triamcinolone is viewed as an active ingredient. Possible effects of chronic exposure to triamcinolone will need to be explored in the safety studies. Furthermore, the contribution of triamcinolone to the efficacy of the product will need to be established.
• Dr. Gooberman was advised to consult regulations on charging for investigational medications. As a number of his patients are involved with the court system, he was also advised to consult regulations on research involving incarcerated subjects. Dr. Gooberman clarified that the subjects were not actually incarcerated; however, treatment with depo-naltrexone was the option suggested by their parole officers as a means to encourage compliance and to show the judge, etc. that they were serious about "kicking" their drug habit.

Minutes Preparer: Tony Chite

Chair Concurrence: Cynthia McCormick

Application: Depo-Naltrexone
Sponsor: Lance Gooberman, M.D.
Type of Meeting: pre-IND

Meeting Chair: Cynthia McCormick, M.D.

Meeting Recorder: Tony Chite

The sponsor’s objective of this pre-IND meeting was to further explore the toxicological and clinical study requirements for marketing approval of depo-naltrexone to block the pharmacological effects of exogenously administered opioids.

April 22, 1999

Cynthia G. McCormick, M.D.
Division of Anesthetic, Critical Care and Addiction Drug Products (HFD-170)
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland 20857

Re: Depo-Naltrexone Meeting

Dear Dr. McCormick:

Thank you for your letter dated April 8 granting our meeting request. Our objective for this meeting is to further explore the toxicological and clinical study requirements for marketing approval of depo-naltrexone to block the pharmacological effects of exogenously administered opioids. Accordingly, enclosed please find our meeting package which reviews the clinical data currently available on this dosage form. We do not intend to address issues related to chemistry or statistics in any detail at this initial meeting.

The safety and pharmacological efficacy of naltrexone in this indication have been established in numerous published studies spanning over 20 years, and effective blood levels of naltrexone for this indication have been reported in the literature. In 1984, the agency found Trexan® , an oral dosage form naltrexone, safe and effective for blockade of the pharmacological effects of exogenously administered opiates. The clinical data relied upon for the approval of Trexan® is indicative of the administrative difficulty associated with formal studies in this patient population.

The Summary Basis of Approval for Trexan® notes the issues involved in studying "treatment efficacy," or the course of opiate dependence. It appears that no such efficacy trials were conducted for Trexan® . Instead, indications of "pharmacologic efficacy" were noted in the published literature. The safety database for Trexan® consisted of approximately 2,000 patients exposed to drug through various open-label studies.

Depo-naltrexone can be expected to act pharmacologically in a manner similar to oral naltrexone. The current pellet formulation has been shown to provide a sustained release resulting in greater than 1 ng/ml naltrexone throughout a 60-day period. As the agency is aware, this level os naltrexone has been shown to be effective in various literature reports. Because drug levels from the sustained release naltrexone pellets are significantly lower than those obtained by oral administration, and orally administered drug is associated with minimal adverse events, it is reasonable to expect that naltrexone pellets will not present additional safety concerns. The safety of several formulations of naltrexone pellets has been demonstrated in over 3,500 patients to date (including over 1,000 patients with the current formulation) for up to seven months with repeated implantation of pellets.

FDA’s May 1998 guidance document entitled "Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products" reviews the quantity of evidence necessary to support effectiveness of drug products. In the second entitled "Extrapolation from Existing Studies," the agency notes that:

While blood levels of depo-naltrexone are not expected to be equivalent to those of oral naltrexone due to the slow release pharmacokinetics of the implantable dosage form, we believe that a conclusion of pharmacological efficacy for depo-naltrexone may be arrived at without further clinical efficacy data. In this regard, we propose to carry out a pharmacokinetic study in healthy volunteers to demonstrate that effective blood levels of naltrexone are achieved. During the same study, we intend to collect safety data on the site of implantation.

We look forward to meeting with the Division on Wednesday, May 26, 9:30 a.m. at your Offices in the Parklawn Building to discuss these issues. Should you require any additional information prior to that time, please feel free to contact me.

Sincerely,

Lance Gooberman, M.D.

cc: Anthony Chite (15 desk copies)
Project Manager