Objective l: Were the facilities and equipment adequate to conduct the study?

This objective is usually met, and the attainment of the objective documented, by the following:

1. Obtaining accreditation for the animal facilities by the American Association for Accreditation of Laboratory Animal Care (AAALAC). (Details on the accreditation program can be obtained from AAALAC, 9650 Rockville Pike, Bethesda, MD 20814, Tel: 301-564-5111, Fax: 301-564 5643). Displaying a current certificate of accreditation in the animal care facilities is adequate proof of compliance.

2. The research facilities should be able to document that the necessary equipment and instruments to conduct the planned research are on hand and in good working order. This is usually done by establishing and maintaining a file containing an inventory of the general laboratory equipment, as well as a list of any special equipment or instruments which are necessary for each protocol.

3. Equipment and instruments used for any study need to be calibrated and maintained properly. Most facilities with only a single site choose to keep one central file which catalogs the common research equipment and appends the calibration, maintenance, and repair records for each piece of equipment. Individual study #is need to document that equipment that requires calibration was, in fact, calibrated at the appropriate frequency.

4. The environmental conditions in the facility including temperature, humidity, and duration of the dark/light cycles to which the animals were exposed should be clearly specified in the protocol and should be entered in the laboratory records. This factor is so important that a central record for the laboratory is usually inadequate, and inclusion of a summary of the environmental conditions in the records of the study is recommended.

Objective 2: Were the origin, identity, condition, and keeping of the animals adequately specified?

How this objective is met will vary with the study, since procedures appropriate to a large rodent study with hundreds of animals may be inappropriate for an abuse liability study in which handlers know each animal by name and have worked with them for years. Nevertheless, certain basic principles apply:

1. Laboratory animals need to be procured in an orderly, controlled, and well-documented fashion, usually from a well established animal breeding facility or another laboratory. The source, species, strain and date of receipt of each shipment of animals needs to be recorded.

2. Laboratory animals obtained from an outside source should be kept in quarantine for 7- 14 days before inclusion in any study. During this period animals should be observed for any clinical sign which may warn that the animal is ill or otherwise unsuitable for inclusion in a specific experiment.

3. Each animal must be uniquely identified in the records. This is best accomplished if upon arrival, animals are numbered upon receipt and assigned to a specific study as soon as possible after quarantine. Needless to say, the experimental data should carry that single unique number for that animal across all treatments, observations, and protocols.

4. Basic information about the health and condition of each animal must be followed over the entire course of the protocol. For example, the body weight of the animals should be determined each time any drug under investigation is administered (to avoid inadvertently giving a different dose as the animal gains or loses weight). Those animals which are used repeatedly for many protocols (e.g. trained monkeys) should be weighed at a periodic rate, and their health condition assessed periodically.

5. Animals in ongoing protocols need to be protected against exposure to injury due to outside influences. Protecting the health status of the procured animals is important to safeguard the health of other animals in ongoing protocols in the same facilities. Animals should be treated prophylactically with vaccines against diseases to which the particular species is most susceptible.

6. Diet should be controlled and standardized. Written standing protocols should be kept for the maintenance of each strain or species studied and a copy appended as appropriate to individual study reports. This is so important in some cases that it is recommended that copies of the procurement receipts for laboratory chows be maintained in the file with the dietary protocols. If special diet is given to any batch of animals (i.e., to deplete a specific neurotransmitter to examine its role on the development of drug seeking behavior), that batch of animals should not be mixed with other animals receiving normal diet. It is also highly recommended that the handling facility have multiple redundant procedures such as putting a display in the handling area identifying animals on special diets as well as labeling the chow and the individual cages.

Objective 3: Was the protocol specific, unequivocal and complete prior to starting the study?

This is the most critical area in evaluating a study. It is common for multiple versions of any given protocol to circulate during the planning of any given experiment. By the start of the experiment the principal investigator and the post-doctoral fellows and staff have all but memorized the study and are extremely loath to write a detailed final version of the protocol. It is essential to realize that it may be several years before the FDA staff receive the results of the study, and the written protocol is the primary record against which the conduct of the study will be judged. Therefore:

1. Before conducting any study, it is necessary that a protocol of the experiment be complete. The protocol should refer to the name and qualifications of the researchers and their supervisors, number of animals per group, doses, controls and parameters to be evaluated. Every protocol must identify a single principal investigator or study director who is personally and professionally responsible for the conduct of the study.

2. Researchers or technicians who will be conducting the study should read the protocol before the experiment, and I is not inappropriate if they submit a signed copy of the final version of the protocol as they understood and executed it as an appendix to the master file at the end of the study.

3. The final protocol should be specific. It should include the number of animals to be use for each condition, the doses to be used, the parameters to be evaluated, the outcomes to be measured, how the data will be collected, stored, checked for quality and analyzed. If off-site analyses are planned (i.e. blood will be drawn to relate the abuse potential with the plasma levels), one should indicate how samples will be handled, analyzed, and their identity verified in the protocol. It is advised that all preliminary experimental designs and protocols be discarded prior to embarking on the study and that ONLY the final version of the protocol be retained in the animal facility and on file.

4. Plans for data management and analysis need to be specified in the protocol. If any animal has been used in a previous study, appropriate reference should be made to that study.

5. Any routine procedure that may affect the condition of the animals needs to be specified, (i.e. procedures adopted for anesthesia) should be discussed in the protocol.

6. It is expected that no study ever goes as planned. Deviations from the protocol need to be indicated in the laboratory data book in an imperishable format as described below.

Objective 4: Were personnel qualified by training and experience to conduct the experiment?

All personnel who conduct scientific and clinical research should have academic credentials, records of training, or evidence of experience appropriate to their duties. For example:

1. It is assumed that the study director and the principal researchers are aware of the scientific basis and methodologies applicable for the specific study. It is expected that all individuals involved in the design or analysis of the study will have a curricula vitae indicating prior experience in experimental and or clinical research relevant to the proposed study.

2. Laboratories involved in training should have a designated individual responsible for each individual in a training status (each junior must have a senior). If the data collected by an individual in a training status is part of a submission for regulatory approval, such data should be countersigned by the supervisor or mentor. No responsible senior may claim to supervise an inappropriate number of individuals in a training status, and should be prepared to document claims of personal supervision of more than five trainees.

3. All personnel, including trainees, should be acquainted with the protocol and experimental procedures. If any protocol involves the use of hazardous materials, carcinogenic compounds, biohazards, or radio tracers, personnel should have documented training, experience, or course work to ensure proper handling of dangerous materials.

Objective 5: Were adequate records kept of how the study was actually performed?

To review a study it is essential that the FDA scientific staff understand exactly what was done in every particular. As has been mentioned, it is likely that few members of the original research team will be available at the facility at the time of review. Therefore it is recommended that the following records or their equivalent be maintained:

1. All experimental data, animal procurement data, weight, gender, diet given, duration of quarantine, animal room temperature, humidity, names of the researchers etc. need to be recorded in an imperishable laboratory note book. If computerized records are kept, hard copy printouts should be made at regular intervals, verified, and attested to as described below.

2. Upon completion of the data collection for each experiment, the principal investigator or study director should verify the raw data with his signature and the date of that action. All data should be recorded in duplicate and one copy should be kept by the study director and the other copy by the researcher or technician who was most directly involved with the experiment.

3. As a general rule, all study data should be reviewed and validated by at least two individuals, both of whom are responsible for the scientific validity of the results. In the event the study director is the principal investigator and conducts the experiment for himself, he or she should validate the results with a peer of equal or superior academic position who is willing to attest to the validity of the work.

4. All records must be kept until reviewed. If the data are submitted to the FDA for product approval purpose (IND/NDA submission) such data and records should be made available to FDA personnel for up to four years after approval of the submission.

5. Any submission of study results to the FDA in either an IND or an NDA should identify by name and position the person who will be responsible for the custody of the study records and will furnish the records upon request to agency personnel.

Objective 6: Were medications and investigational drugs handled properly?

Every investigator who has handled investigational or blinded medications in research knows of the potential problems involved in mis-identification or contamination of research supplies. FDA scientific staff need to be able to assure themselves, from the records, that the right drugs were given to the correct animals in the right dose at the right time. Therefore:

1. The research facility should keep and store sufficient amount of drugs needed for the research while avoiding long-term storage of excess quantities. All investigational drugs should be properly labeled and stored under recommended conditions and the label should include the source of the drug (code # or lot #).

2. A log book or file should be maintained for each investigational drug to indicate source, lot or code number, and amount of the drug received for testing and the amount used for each experiment. Each time the drug substance is weighed for the purpose of the experiment, it should be noted in the log book with signature of the person who weighed or used it and the date. Accounting for clinical supplies is an essential part of quality control and it is expected that the amount used will be equivalent to the amount received after making due allowance for wastage.

3. After each experiment the unused drug or its solution should be labeled and stored appropriately if it has to be used for the next experiment, or discarded if it is unusable. The investigator should obtain stability information for any drug or solution which is kept for repeated use.

4. If prepared drug or solution needs to be discarded, the approximate volume or amount should be recorded in the log book. Unless the solution is of known environmental hazard and/or radioactive, it can be flushed under water into the sink (unless to do so is contrary to local law or facility practices). Compounds which possess known abuse potential should be flushed in the presence of a peer, the study director, or a designated person.

5. Radiolabelled or carcinogenic drugs, biohazards, solutions, tissues used with Radiolabelled drug substance, spillage, and secretions should be discarded into specified containers in a manner recommended for such disposal in appropriate regulations.

It is possible that many drugs which are candidates for abuse liability testing may have great potential to induce addiction and chemical dependency. In order to ensure that these drugs do not reach the population from the testing laboratories, appropriate measures need to be taken. These may include:

1. Keeping the smallest practical quantity of the drug at the testing site.

2. Keeping the main clinical supply in a safe place and under lock and key. (The keys should be made available only to the study director and the principal investigator).

3. Any individual engaged in research on abuse liability testing of already scheduled drugs (as comparator or controls) should follow the guidelines of 21 CFR 1300 on registration of manufacturer, distributors and dispensers of controlled substances.

Objective 7: Were the responsibilities of each party for the work clearly attributed and accepted?

One purpose of this guideline is to help the investigator (or study director) assure a commercial sponsor of a protocol that the FDA is likely to accept the results of a study for review. In the GLP regulations there are specific requirements that toxicological studies be audited by a reviewer independent of the organization who attests to the validity of the work. This level of independent review is not appropriate to properly conducted academic research, but both sponsors and investigators have specific responsibilities for work that is to be submitted to the FDA.

The responsibility of the sponsor of the research is to select qualified investigators, provide them with the information and material required to conduct an investigation properly, ensure proper monitoring of the research, ensure that the study is conducted in accordance with the investigational plan and protocols, and that appropriate records are maintained and available for studies conducted in support of submissions to the agency.

Specifically, sponsors are usually expected to:

a. Select only investigators qualified by training and experience to investigate the drug.

b. Obtain the following before permitting an investigator to begin participation in an investigation intended to support submissions to the agency:

1. A signed statement with the name and address of the investigator;
2. The name and address of any animal welfare agency, review board, committee or other body tasked with oversight of animal research at the facility;
3. The name and address of any research facility(ies) where the investigation(s) will be conducted;
4. A commitment by the investigator that he or she:
• (a) Will conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect safety of the animals or the investigators or the validity of the research;
• (b) Will personally conduct or supervise the described investigation(s);
• (c) Will report to the sponsor adverse experiences that occur in the course of the investigation;
• (d) Will establish and maintain such records as are required to support the proposed study in later submissions of the data to the FDA;
• (e) Will open the records of the study and the physical facility to inspection by representatives of the sponsor and the FDA as required to support the validity of the data.

5. Monitor the progress of all ongoing investigations being conducted that are intended to support submissions to the agency. If a sponsor discovers by such monitoring that the investigator is not complying with the research agreement, or is not properly conducting the study, and such non-compliance cannot be resolved, the sponsor is expected to discontinue shipment of drug and support of such research and notify the agency of this event.

6. Maintain adequate records of drug shipments to the investigator, verify the existence of appropriate licenses for the possession and use of any controlled substances, verify the appropriate return of disposal of investigational supplies, and retain such records for the appropriate periods as elsewhere specified.

7. Maintain the records of the study and make them available to FDA inspectors or to review personnel as appropriate.

Although the majority of the burden for record-keeping and quality assurance usually rests with a commercial sponsor who plans to use the data in support of a commercial application, all of the duties of the sponsor as described above may be met by the investigator, if they have made provision for independent monitoring of the study by a peer as described above.

Nevertheless, it is a principle within the agency that a scientist assume personal responsibility for the integrity and validity of his or her research. The principal investigator (or designated study director) is responsible for the conduct of the study, the welfare of the animals, acquisition, control and disposal of the investigational drug(s), submission of adequate progress reports to the sponsor, immediate notification of any findings that may directly reflect on the safety of the drug in human studies, and timely submission of the final report. This may be accomplished in a number of ways, but the most convenient is for the principal investigator, study director, or independent peer to submit a properly completed copy of the enclosed "Good Research Practices" checklist which includes a statement that he has personal custody of the raw data, verified its scientific accuracy, and will maintain the data and make it available to the FDA for the appropriate period. A copy of this checklist signed by the investigator, may be submitted to the FDA along with the data, and provides substantial evidence of compliance with these guidelines.

Objective 8: Was the validity of the work confirmed by adequate supervision?

The validity of scientific results is usually determined by how well the findings withstand careful scientific scrutiny. Unlike most general scientific research which is either confirmed or disproved by future work by other scientists, most medication development work will never be replicated (much of it may not even be published). This means that the FDA review is the only substantive peer review such work will ever receive. Acceptance of this responsibility by the agency has led to the establishment of a Division of Scientific Investigations that inspects the facilities, records, and results of studies submitted to the FDA. Not all studies are selected for audit but every site that conducts studies which will be submitted to the FDA in support of an IND or NDA must allow inspection. At such an inspection the investigator will determine the extent to which the research met the objectives of these guidelines. In general, this will be accomplished by:

1. Examination of the facilities and verification of accreditation.
2. Examination of animal procurement, quarantine and identification.
3. Verification of proper housing, proper anesthesia and humane treatment.
4. Comparison of the protocol at the site against the last version filed with the FDA.
5. Inspection of the logbooks for compliance with the protocol.
6. Determination of how frequently animals are entered in multiple protocols.
7. Examination for evidence of adequate supervision by the principal investigator.
8. Evidence of good data handling, verification, and quality assurance procedures.
9. Notification of the study director of any deficiencies.
10. Issuance of a certificate of satisfaction for the study.

Unlike the current GLP requirements, any research or testing done under these guidelines need not be certified by an independent quality assurance unit, however, either the commercial sponsor or the study director will verify the overall integrity, quality of the study and record keeping as described above.

Although it is extremely rare in academic faculties, there are occasions where such serious deficiencies are found on inspection as to make it impossible to be certain of the validity of the results produced by a given laboratory. In such cases the quality assurance unit of FDA will report the deficiencies of the facilities and other identified problems related to the study to the review division within FDA as well as to the study director, principal investigator, academic institution, and sponsor. The responsible parties are required to respond within six months and explain how the deficiencies with this and future studies will be addressed. Failure to provide satisfactory response to the deficiency letters or to reach an agreement with the agency as to how to correct the situation may disqualify the laboratory from conducting any studies intended for submission to the FDA until the situation is resolved.

This guideline has been proposed to assure the high quality of research and testing in the evaluation of the behavioral pharmacology or the abuse liability assessment of new medications in academic settings. Any suggestions should be addressed to:

Director

Pilot Drug Evaluation Staff (HFD-007)

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

Enclosure: Certification checklist

Page 1

Format of the Checklists:

1. List of experiments and instruments necessary for the experiments and surgical procedures. Record to show when these equipments/instruments were serviced, if any. The protocol should state that listed equipments and instruments are in working condition at the time of experiments and inspection.

Description of the Item; Dates serviced; Present condition; Location of Records

2. Temperature, humidity and duration of light/dark cycles in the animal quarters and laboratories during the experiment.

Dates; Temp; Humidity; Light/Dark

Page 2

3. Date of purchase of animals, species, sex and strain and body weight. Number of animals received in each shipment.

Vendor; Species; Sex; Weight; Protocol; Location of Record

4. Quarantine period for animals with dates

5. If any animal was used in a separate experiment, dates of the experiment and brief description of the experiment would be provided.

6. If monkey is used in the experiment, a statement should include to refer whether any laboratory assessment was done for a possible virus infection during quarantine period.

7. Nature of the diet given to the animals.

Nature of Diet; Batch #; Date of Purchase and Vendor; Location of Record

Page 3

8. Volume and page numbers of the record books in which raw data are entered. Each page of the record should be signed by the experimenter and the study director.

Protocol #; Notebook #; Pages

9. Name of the Investigational drug and total amount used to complete the project or protocol.

Entry in Lab Notebook Pages #; Dates; Name of the compound; Amount used

Signature of the Study Director; Date

Name:

Position:

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