Source: https://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm120265.htm
Timestamp: 2019-04-25 16:16:24+00:00

Document:
AGENCY: Food and Drug Administration.
SUMMARY: The Food and Drug Administration (FDA) is issuing final regulations to amend its current bioavailability/bioequivalence regulations to require the retention for a specified period of reserve samples of the drug products used to conduct certain bioavailability or bioequivalence studies submitted in support of the approval of new drug applications (NDA's) and abbreviated new drug applications (ANDA's), and when specifically requested, to release the reserve samples to FDA. The requirement applies to manufacturers who conduct in-house bioavailability and bioequivalence testing and to testing facilities who conduct such testing under contract for a drug manufacturer. The requirement also applies to foreign manufacturers who conduct their own studies for new drug product approval and to foreign testing facilities under contract for a U.S. manufacturer or foreign manufacturer. This action is intended to help ensure bioequivalence between generic drugs and their brand-name counterparts and to help the agency investigate more fully instances of possible fraud in bioavailability and bioequivalence testing. This final rule adopts the interim rule published in the Federal Register of November 8, 1990, with minor changes based on comments the agency received on the interim rule.
DATES: Effective May 28, 1993. Submit information on the Economic Impact section of this document (section III.) by May 28, 1993.
ADDRESSES: Submit information on the Economic Impact section of this document to the Dockets Management Branch (HFA-305) Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Marilyn L. Watson, Center for Drug Evaluation and Research (HFD-360), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-295-8038.
SUPPLEMENTARY INFORMATION: In the Federal Register of November 8, 1990 (55 FR 47034), FDA published interim regulations to require the retention for a specified period of reserve samples of the drug products used to conduct bioavailability or bioequivalence studies of drug products, and when specifically requested, to release the reserve samples to FDA. The interim regulations were effective on the date of publication. FDA provided 60 days for public comment. The final rule incorporates all of the main provisions of the interim rule; the agency has made a number of minor clarifying changes in response to the comments received on the interim rule.
Highlights of the final rule are summarized below, followed by a summary and discussion of the comments.
In the November 8, 1990, interim rule, the agency codified requirements regarding the retention of bioavailability and bioequivalence testing samples as part of the bioavailability/ bioequivalence regulations existing at that time by adding §§ 320.32 and 320.63 (21 CFR 320.32 and 320.63), and by adding conforming amendments to § 320.31 (21 CFR 320.31) and to FDA's investigational new drug application (IND) and NDA regulations, new §§ 312.57(c), 314.125(b)(17), and 314.150(b)(9) (21 CFR 312.57(c), 314.125(b)(17), and 314.150(b)(9)). The purpose of these new requirements is to make available to FDA reserve samples of tested products for analysis to ensure that the bioequivalence and bioavailability results upon which FDA bases approval of NDA's and ANDA's are reliable. The rule also permits the agency the discretion to refuse to approve and to withdraw approval of an application if an applicant or testing laboratory refuses to permit an inspection of the facilities or records relevant to a bioavailability or bioequivalence study or to release to FDA reserve samples when requested.
In the Federal Register of July 10, 1989 (54 FR 28872 at 28911), FDA proposed changes in the regulations in existing 21 CFR part 320. Those proposed changes would, among other things, remove subpart C and those regulations that apply to establishing a bioequivalence requirement, move to subpart B the remaining regulations under existing subpart C, and where appropriate, combine the remaining regulations with the existing subpart B regulations. In the Federal Register of April 28, 1992 (57 FR 17950 at 17997), the proposed new subpart B structure was issued as a final rule. The agency is now conforming this rule to the new subpart B structure.
The final rule applies to domestic and foreign sponsors and applicants (hereinafter called a study sponsor) who perform in-house bioavailability or bioequivalence testing for new drug product approval under an NDA, ANDA, or supplemental application and to any domestic and foreign testing facility that performs such bioavailability or bioequivalence testing under contract (contract research organization) for a study sponsor.
A study sponsor or contract research organization, whoever performs bioavailability or bioequivalence testing for new drug product approval, must retain a reserve sample of each test article and reference standard used to perform in vivo bioavailability or in vivo or in vitro bioequivalence studies that is representative of each batch of the test article and of the reference standard provided by the study sponsor for the testing. The final rule clarifies the types of in vivo bioavailability and bioequivalence studies for which reserve samples are to be retained. The study sponsor or contract research organization will retain a sufficient quantity of each reserve sample of the test article and of the reference standard to permit FDA to perform five times all of the release tests required in the NDA, ANDA, or supplemental application. In addition, each reserve sample is required to be: (1) Adequately identified so that it can be positively identified as having come from the same sample as used in the specific bioavailability or bioequivalence study, (2) stored under specified conditions, and (3) retained for a specified period. An ambiguity in the interim rule regarding storage conditions has been clarified to accurately reflect the agency's intent. In addition, the final rule also includes a provision for the transfer of reserve samples when a contract research organization goes out of business.
Ordinarily, the reserve samples, or a portion of the reserve samples, will be collected by an FDA investigator at the place of storage during a preapproval inspection of the facilities involved in manufacturing the test article and of any contract testing facility that conducts bioavailability or bioequivalence testing for the study sponsor. Where FDA has reason to believe fraud was involved in performing a bioavailability or bioequivalence study that was [*25919] conducted by a foreign testing facility, the facility may be asked to consent to FDA inspection or to submit to FDA reserve samples of the products used in the study.
Because access to test samples and related records may be essential to assess the validity and reliability of the results of a required bioavailability or bioequivalence study, the final rule, like the interim rule, adds as a reason for refusing to approve an application and as a circumstance under which FDA has discretion to withdraw approval of an application, refusal to permit an inspection of the facilities or records relevant to a bioavailability or bioequivalence study contained in an application or to submit or release reserve samples when requested by the agency.
FDA received 27 comments on the interim rule. The comments came from pharmaceutical manufacturers, trade associations, a professional group, and contract testing facilities. Most of the comments raised questions or concerns about the reserve sample retention period, quantity of the samples to be retained, and storage requirements for the samples. Several comments requested clarification of the types of in vivo bioavailability studies for which test samples would have to be retained under the new rule. Comments also were received in response to the agency's questions about whether additional requirements were necessary to ensure that the integrity of the reserve samples is not compromised during the retention period.
A. Definition of an "NDA Biobatch" and an "ANDA Biobatch"
l. A number of comments requested clarification of the types of bioavailability studies from which test samples would have to be retained. The comments asked whether the many types of clinical pharmacology, pharmacokinetic, and pharmacodynamic studies in which blood samples are routinely collected for analysis would be considered bioavailability studies for purposes of this rule. Some of the comments suggested that reserve samples be retained only from studies which define the absolute or relative bioavailability of a new drug and studies necessary to demonstrate the bioequivalence of a new formulation to that which was previously studied in clinical trials.
One comment asserted that sample retention should be limited to the lot of test and reference formulations used in the pivotal bioequivalence study. The comment stated that, in the case of an NDA, this would be the lot of the product used in the study or studies conducted to demonstrate equivalence between the investigational formulation(s) and the formulation proposed for marketing. For an ANDA or supplemental application, this would be the study conducted to demonstrate equivalence between the currently marketed form and that proposed for marketing.
Two comments asked whether reserve samples should be kept for all in vivo "biostudies," whether or not the studies were submitted in support of the approval of an application or only for those studies required for approval of an application. The comments" question was based on a perceived conflict between the language of the interim rule at § 320.32(a) (requires retention of samples used in an in vivo bioavailability study "required for approval of the application or supplemental application"), §§ 312.57(c) and 320.31(d)(1) (requires sponsors of all IND's for "biostudies" and persons conducting such studies under an exemption from the IND requirements to retain samples of the products tested, "in accordance with * * * § 320.32"), and § 320.63 (retention of samples is required for products used in an in vivo or in vitro bioequivalence study "required for approval of, or submitted in support of the approval of, the full or abbreviated application or supplemental application * * * in accordance with * * * § 320.32." The comments further asked whether the requirements apply to in vitro studies, noting that § 320.63 refers to sample retention for certain in vitro studies in accordance with § 320.32, but § 320.32 does not apply to in vitro studies.
n1 Compliance Program 7346.832 is available at cost from the Freedom of Information Staff (HFI-35), Food and Drug Administration, rm. 12A-30, 5600 Fishers Lane, Rockville, MD 20857.
a. NDA. (i) If the formulation of the applicant's proposed drug product (test article) is the same as the formulation(s) used in the pivotal clinical studies, the applicant would retain a reserve sample from the batch of the test article used to conduct an in vivo bioavailability study comparing the test article to a reference oral solution, suspension, or injection. A reserve sample of the reference standard (oral solution, suspension, or injection), which is usually made up when needed for a study, would not be retained. If the bioavailability study needs to be repeated, the reference standard would be prepared at the time of the study. For purposes of this rule, pivotal clinical studies are those adequate and well-controlled studies necessary to establish the safety and effectiveness of the test article for its claimed indications.
(ii) If the formulation of the test article differs from the formulation(s) used in conducting the pivotal clinical studies, the applicant would retain a reserve sample of the test article and of the reference standard from the batches used to conduct an in vivo bioequivalence study comparing the test article to the formulation(s) (reference standard) used in the pivotal clinical studies.
(iii) For a new formulation, new dosage form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved for marketing, a reserve sample of the test article and of the reference standard would be retained from the batches used to conduct an in vivo bioequivalence study comparing the test article to a marketed product (reference standard) that contains the same active drug ingredient or therapeutic moiety.
For an NDA, test article means the drug product for which the applicant is seeking approval. Reference standard has the same meaning as the term reference material in § 320.25.
b. ANDA. Reserve samples of the test article and reference standard would be retained from those batches used to conduct an in vivo bioavailability or an in vitro study comparing the test article to the approved drug product upon which the applicant relies for approval of its proposed product to establish their equivalence.
For an ANDA, test article means the drug product for which the applicant is seeking approval. Reference standard means an approved drug product identified by FDA as the drug product upon which an applicant relies in seeking approval of its ANDA and is usually the innovator product.
The agency has revised the final rule at §§ 312.57(c) and 320.38 (§ 320.32 in the interim rule) to clarify the in vivo bioavailability studies from which reserve samples are to be retained. With [*25920] respect to the reference to in vitro studies in § 320.63, but not in § 320.32 of the interim rule, FDA included the two new sections such that they would conform to the then existing structure of 21 CFR part 320. Former subpart B of part 320 addressed procedures for determining the in vivo bioavailability of drug products whereas former subpart C of part 320 addressed bioequivalence requirements, which may be an in vivo or an in vitro test. Section 505(j) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355(j)) requires that an ANDA include information to show that the drug product for which the applicant is seeking approval is bioequivalent to the approved drug product upon which the applicant relies in seeking approval of its abbreviated application. Bioequivalence may be demonstrated by in vivo or in vitro bioequivalence methods as determined by the agency. Thus, the reference to an in vitro study in § 320.63 was necessary to accommodate ANDA's submitted under section 505(j) of the act. Because the rule applies to bioavailability and bioequivalence studies required for approval of an NDA and an ANDA, § 320.63 has been revised to delete the wording "or submitted in support of the approval of." Section 320.63 also has been revised to remove the reference to a full application which is covered by § 320.38.
Section 320.31 exempts from the requirements of part 312 many bioequivalence and bioavailability studies. The interim rule added as a condition for such an exemption that the sponsor, or any contract research organization to whom the sponsor delegates responsibility to conduct a bioequivalence or bioavailability study, retain reserve samples of the test article and reference standard and release them upon request to FDA (55 FR 47034 at 47036 and 47038). In finalizing the new subpart B structure of 21 CFR part 320, FDA inadvertently omitted this provision. Therefore, FDA has revised § 320.31 to retain the requirements set forth in the interim rule and to clarify the in vivo bioavailability studies from which reserve samples are to be retained.
2. One comment requested that the regulations at §§ 314.125(b)(17) and 320.63 be revised to clarify that the regulations apply only to a pivotal bioequivalence study. The comment also asserted that § 320.32 (§ 320.38 in this final rule) be deleted because a "pivotal" bioavailability study is technically a bioequivalence study and retention of samples from this study is discussed in § 320.63.
The agency agrees with the comment regarding § 314.125(b)(17) and has revised the final rule accordingly. The agency's conclusions on the types of bioavailability and bioequivalence studies for which the requirements apply and its revisions to §§ 320.38 and 320.63 are discussed in section II.A.1.
3. One comment suggested that, in the case of multiple "biostudies" usually conducted in sequence for a single NDA or ANDA (i.e., a sustained release product) using the same lot of a product, the regulations specify that one supply of retention samples be provided to the testing facility in sufficient quantity for all studies. The comment also asked whether, if additional supplies of the product are needed, the full amount of retention samples also must be supplied again.
FDA believes that the comment misunderstood the interim rule with respect to how the reserve sample is obtained by a contract testing facility. If bioavailability or bioequivalence testing is performed under contract, the study sponsor provides the testing facility with a supply of the test article and of the reference standard sufficient for the testing facility to conduct the study or studies and to remove a portion of the test article and of the reference standard for retention as reserve samples. FDA did not intend that the study sponsor separate out the reserve samples of the test article and reference standard prior to sending the batches to the testing facility. This is to ensure that the reserve samples in fact are representative of the same batches provided by the study sponsor for the testing.
a. If a single container of the test article and of the reference standard is provided to the testing facility, the testing facility should remove a quantity of the test article and of the reference standard from their respective container sufficient to conduct the study; the remainder of each container would be retained as the reserve sample in the original container.
b. If multiple containers of the test article and of the reference standard are provided to the testing facility, the testing facility should randomly select enough containers of the test article and of the reference standard to conduct the study; the remaining containers of the test article and of the reference standard would be retained as the reserve sample in the original containers.
c. If the test article and reference standard are provided to the testing facility in unit dose packaging, the testing facility should randomly select a quantity of unit doses of the test article and of the reference standard sufficient to conduct the study; the remaining unit doses of the test article and of the reference standard would be retained as the reserve samples in the original unit dose packaging. Providing the test article and reference standard in unit dose packaging for conducting the study and in bulk containers for all of the reserve samples would not be acceptable because it prevents the testing facility from randomly selecting the reserve samples. However, as an alternative for the reserve samples, the study sponsor may provide the testing facility with a quantity of unit doses of the test article and of the reference standard equal to at least 24 dose units and the remaining quantity sufficient to retain the "five times quantity" in bulk containers.
d. If the study is to be blinded and the test article and reference standard are provided to the testing facility in unit dose packaging, with each unit dose labeled with a randomization code, the study sponsor must provide the testing facility with a labeled set of the test article and reference standard sufficient to conduct the study and with additional, identically labeled sets sufficient to retain the "five times quantity." The testing facility should randomly select a labeled set to conduct the study; the remaining labeled sets would be retained in their unit dose packaging as the reserve samples. For a blinded study, the study sponsor should also provide to the testing facility a sealed code for use by FDA should it be necessary to break the code.
If the same batches of the test article and of the reference standard initially provided to the testing facility are used in performing more than one study, only one reserve sample of the test article and reference standard in sufficient quantity need be retained. The reserve samples must be identified as having come from the same batches as used in each specific study. However, if additional supplies of the test article [*25921] and of the reference standard are needed by a testing facility for performing additional studies, the testing facility must retain the required reserve samples from the subsequent shipment regardless of whether the shipment is from the same batch as that previously provided to the testing facility. This is to ensure that the reserve samples are, in fact, representative of the batch provided by the study sponsor to the testing facility.
4. One comment stated that FDA may request additional "biostudies" after submission of an ANDA and a firm may want to use the same lot of test and reference products as was used in conducting the original study. The comment argued that under the strict retention sample requirement, the firm could not conduct these biostudies without depletion of the retention samples.
In the situation described by the comment, the study sponsor would need to use a different batch of the test and reference products to conduct additional studies if supplies of the batches used to conduct the original studies are depleted. The regulations do not permit a study sponsor or contract research organization to use its reserve samples to conduct the additional studies.
5. Several comments requested clarification of the regulations about who is responsible for reserve sample retention. One comment argued that the logical responsible party for long-term retention of samples should be the applicant because the applicant is responsible for the manufacture, packaging, testing, and release of the sample of the test article and minimally the packaging, identification testing, and release of the reference standard. The comment stated that it is not practical to sufficiently control the conditions of storage, sample stability, and sample retention at a contract facility after the completion of a study. One comment argued that some outside testing facilities such as universities, hospitals, and clinics do not have the space or proper environment to hold the reserve samples at all or to hold them at the study location, and many do not have the authority to hold certain reserve samples such as controlled substances. Another comment suggested that the regulations provide for the use of independent, third party organizations for the storage of reserve samples. Still another comment stated that the applicant should have the option of storing reserve samples at a company facility rather than at a contract laboratory.
The agency reaffirms that reserve sample retention is the responsibility of the entity performing the bioavailability or bioequivalence study. If the study sponsor performs the study, it is responsible for reserve sample retention for that study; if a study is performed under contract, the contract research organization retains the reserve samples. The purpose of this requirement is to eliminate the possibility for sample substitution by the study sponsor or to preclude a study sponsor from altering a reserve sample from a study conducted by a contract research organization prior to release of the reserve sample to FDA. In several instances, FDA has found that a study sponsor provided the contract testing facility with disguised innovators" products rather than its own proposed product as the test product in certain bioequivalence studies. The reserve samples collected by FDA must have come from the batches provided by the study sponsor to the testing facility for performing a bioavailability or bioequivalence study.
The agency advises that a contract research organization may contract with an independent, third party to provide storage for reserve samples if the contract research organization does not have facilities to store the samples under conditions consistent with product labeling. In this situation, the contract research organization shall provide to the study sponsor, for submission in the bioavailability or bioequivalence study data, the name and address of the facility at which the reserve samples will be stored. A new paragraph (h) is added to § 320.38 to include this provision. The agency notes that hospitals and clinics may wish to consider using their pharmacies for storage of the reserve samples.
With respect to retention of reserve samples that are controlled substances, the burden is on the person who is responsible for retaining the samples to comply with all applicable requirements of the Controlled Substances Act (21 U.S.C. 801) and its implementing regulations.
6. One comment asked who had responsibility for reserve sample retention when a contract research organization administers the drug and collects biological samples, but the biological samples are then returned to the applicant for analysis.
For purposes of this regulation, the agency would consider the contract research organization to have conducted the study and to be responsible for retaining the reserve samples. Similarly, if one contract research organization administers the drug and another contract research organization performs an analysis of the biological samples, the contract research organization that administers the drug would retain the reserve samples.
7. Numerous comments addressed the length of the sample retention period. The interim rule requires that reserve samples be retained for a period of at least 5 years following the date on which the application or supplemental application is approved, or, if such application or supplemental application is not approved, at least 5 years following the date of completion of a bioavailability or bioequivalence study. The interim rule specifically requested comment on the appropriateness of the retention period.
Most of the comments expressed concern that most reserve samples would not exhibit the stability necessary to maintain strength, quality, and purity over such a prolonged period of time, and, therefore, there could be no guarantee that the samples would be appropriate for evaluation by FDA as intended by the interim rule. Requiring special storage conditions, e.g., refrigeration or dehumidification, to prolong a product's stability beyond its normal shelf life would result in a significant expenditure to the applicant or contract research organization responsible for sample retention. Some comments noted that the 5-year period only begins when the application is approved and, in terms of real time, this could be 6 to 8 years for a generic drug product and 7 to 12 years for a new chemical entity. One comment suggested 3 years rather than 5 years as an appropriate retention period; another comment suggested 2 years past submission of an application or supplement, or until the application is approved, whichever occurs first. One comment suggested that FDA make the sample retention period consistent with the good laboratory practice regulations in 21 CFR 58.195(b) and (c). Another comment suggested a retention period of 5 years from the date the bioavailability or bioequivalence study was completed, arguing that NDA and ANDA approval dates are not routinely communicated to a contract testing facility due to potential conflicts of interest.
The 5-year reserve sample retention period is intended to permit flexibility by FDA in its collection and testing of retention samples. Ordinarily, the reserve samples, or a portion of the reserve samples, will be collected by FDA personnel directly from the study sponsor or contract research organization at the storage site during a [*25922] preapproval inspection. FDA's priorities for preapproval inspection and sample collection include narrow therapeutic range drugs, new chemical entities, and generic versions of the 200 most prescribed drugs. For drug products not represented in one of these priority categories, a preapproval inspection would be triggered when the applicant's manufacturing facility is new or has not been recently inspected, and when the NDA or ANDA is the initial application for the applicant. In those cases where preapproval inspections were not conducted and reserve samples were not collected prior to approval of an application or abbreviated application, retention of the reserve samples for the 5-year period would permit their availability for collection and testing after approval. Thus, any retention period that would not continue beyond the approval date of an application, as suggested by some comments, would be unacceptable because it would not provide for the availability of the samples in those situations where a preapproval inspection and sample collection were not conducted or where questions arose after approval about a study sponsor's bioequivalence or bioavailability data.
The agency recognizes that a product retained beyond its normal shelf life may not exhibit the stability necessary to maintain its identity, strength, quality, and purity. However, certain types of analyses can be performed on a product to determine that the test article was indeed used in performing a bioavailability or bioequivalence study and that there was no substitution of the reference standard for the test article. Generally, the formulation of the test article and reference standard will differ. For example, different excipients such as binders, fillers, and lubricants may be used; and products may contain tracer ingredients that are unique to the identification of a particular product. Appropriate analyses can be performed on a product retained beyond its expiration date to detect these differences.
8. One comment asked that FDA clarify in the rule that the retention samples may be kept in any appropriate container and need not necessarily duplicate the containers for the products used in the "biostudy." The comment stated that, in many studies, the drug supplied is packaged in individual unit doses or small bottles containing a single day's supply for each study participant. In such cases, if 500 doses are needed for the retention sample, an appropriately packaged bottle of 500 should be allowed, i.e., not 500 unit doses. Another comment recommended that solution dosage forms, parenterals, inhalation aerosols, biologicals, and other specialized delivery devices where storage, stability, and security could be problematic be excluded from retention status.
FDA does not agree that retention samples be kept in any appropriate container. The reserve samples should be retained in the same container/closure system in which the study sponsor provides to the testing facility the supplies of the test article and reference standard. This will provide to FDA evidence as to how the supplies of the test article and reference standard were received by the testing facility. As noted in section II.A.3, the study sponsor should provide to the testing facility supplies of the test article and of the reference standard packaged such that the reserve samples can be randomly selected by the testing facility and retained in the study sponsor's container/closure system.
The agency disagrees with the comment suggesting that certain dosage forms be excluded from the reserve sample retention requirement. The agency must have adequate assurance that the bioavailability and bioequivalence results upon which FDA bases approval of an application are reliable. Therefore, reserve samples of all products used to conduct the types of bioavailability or bioequivalence studies described in this rule must be available for later examination/analysis by FDA.
9. One comment suggested that reserve samples be stored according to the approved labeling and that this be clarified in the rule. Another comment stated that, for new development compounds, appropriate storage information is not always available during the early stages of development, or if it is, such storage conditions are usually limited or restricted. In such a case, storage is usually in accordance with the sponsor's storage requirements.
The agency did not intend that special storage conditions be provided to prolong a product's stability beyond its normal shelf life. All reserve samples are to be retained and stored under conditions consistent with product labeling. The agency believes that, for the types of bioavailability and bioequivalence studies described above for which reserve samples are to be retained, appropriate storage information will be available in the product's labeling. Section 320.38(e) of this final rule (§ 320.32(c) of the interim rule) has been revised to require storage under conditions consistent with product labeling.
10. One comment argued that, for a contract research organization, determining the starting date for sample retention is often a problem because the contract research organization does not have direct knowledge or control over such events as discontinuance of a compound's development, submission of an application for approval, or approval of an application for marketing, which initiates the 5-year retention period.
The agency believes that a contract research organization can make arrangements with a study sponsor regarding notification of the status of the application for which a bioavailability or bioequivalence study has been conducted, and that it is the responsibility of the contract research organization to obtain such information in order to comply with the sample retention requirements of this rule. There is nothing in the regulations that prevents the inclusion, in the contract between a study sponsor and a contract research organization, of a condition requiring the study sponsor to notify the contract research organization of those regulatory actions about a test article that are necessary for a contract research organization to comply with this rule, e.g., discontinuance of the development of a drug, submission of an application for approval, or date of approval of an application for the test article. Thus, the agency recommends that all contract research organizations insist on the inclusion of such a condition in their contract with the study sponsor.
11. One comment stated that the reference standard used for determining bioavailability is usually a solution or suspension that is made up especially for the study, which would rarely be expected to be stable for more than 6 years. The comment suggested an exemption from the sample retention requirements for these reference standards.
As discussed under section II.A.l.a.(i), a reserve sample of the reference standard from the batch used to conduct a bioavailability study comparing the test product to a reference oral solution, suspension, or injection need not be retained. If the study needs to be repeated, the reference standard would be prepared at the time of the study.
12. One comment asked if the 5-year sample retention requirement would apply if, after receiving a not approvable letter from the agency, the applicant decides to withdraw the NDA.
The final rule, like the interim rule, requires that if an application or supplemental application is not approved, reserve samples be retained at least 5 years following the date of [*25923] completion of the bioavailability or bioequivalence study in which the sample, from which the reserve sample was obtained, was used. A decision by the applicant to withdraw its application in response to a not approvable letter is without prejudice to refiling. Therefore, because an applicant may resubmit its application, data from previously conducted bioavailability studies could be used for approval of the resubmitted application. Thus, in the situation described by the comment, the reserve samples must be retained for the required time period. The agency believes, however, that in some cases, given the time that may elapse between the conduct of a study and the completion of FDA's review of an application, the 5-year period following the date of completion of a bioavailability study will have expired.
13. One comment asked if the agency would grant a waiver reducing the reserve sample amounts if sufficient quantities of a drug product were not available due to production restrictions such as high product costs or high potency compounds.
The agency does not intend to grant waivers from the requirements of this rule. FDA must be assured that the bioavailability and bioequivalence results upon which FDA bases approval are reliable. Therefore, samples of the products used to conduct the types of bioavailability and bioequivalence studies described in this rule must be available for FDA's analysis. An applicant should consider the requirements of this rule in determining its production quantities.
14. The interim rule required that a sufficient quantity of the reserve samples be retained to permit FDA to perform five times all of the release tests required in the application or supplemental application.
Several comments argued that the quantity of both the test article and reference standard seemed excessive, and asked the agency to reconsider the retention sample size requirement in light of the intended uses for the retained samples. Some comments suggested that the regulations be modified to reflect either the requirement of twice the quantity needed for release testing under the current good manufacturing practice (CGMP) regulations, or the NDA methods validation requirement in 21 CFR 314.50(e) of three times the quantity necessary to perform each test. Two comments argued that samples of the reference standard usually are obtained from the marketplace, and it can be extremely difficult to find in large quantities a single lot of a product sufficient to conduct the study and to retain a portion for the reserve sample. One of the comments suggested retention of two intact bottles of the reference standard sample for identification of lot number, expiry, strength, etc., for 3 years.
One comment asserted that acquiring large quantities of material, if available, for no purpose other than satisfying an excessive retention requirement is an unnecessary economic cost. In addition, the comment suggested that, in assessing potential uses, the agency consider that: (1) the materials to be tested may have been well into their anticipated shelf life at the time of the bioavailability or bioequivalence testing, and (2) the materials will inevitably continue to deteriorate over time such that many potential tests of the retained material (e.g., rerun of release tests or of the "biostudy" itself) could well be meaningless even if those retests are conducted during the application review process. Another comment asserted that the regulation will cause an economic impact in that additional storage space will need to be obtained and existing space modified in order to meet unique and long-term storage requirements. One comment stated that it may not be practical to retain the five times quantity for special dosage forms in limited supply such as early development lots for bioavailability studies.
FDA's experience in the testing of reserve samples of drug products used in a bioavailability or bioequivalence study is that the five times quantity required for the test article and the reference standard is needed to perform necessary testing. Although the interim rule required a "sufficient quantity to permit FDA to perform five times all of the release tests required in the application or supplemental application," FDA does not intend to perform release tests on the reserve samples. The five times quantity standard is intended to provide a yardstick for the retention of a sufficient quantity of the samples by all study sponsors and contract research organizations. The reserve samples of the test article and of the reference standard are used by FDA to conduct a chemical and physical examination of the samples to assure the identity and composition of the test article and reference standard. This is necessary to detect fraudulent substitution of the reference standard for the test article in conducting a bioavailability or bioequivalence study. Although generic drugs are expected to be functionally equivalent to their brand-name counterparts, they are not expected to be identical in all physical and chemical aspects because of differences in, for example, identity and proportions of excipients. These differences are used by FDA to determine if fraudulent substitution has occurred. Any remaining reserve sample is held by FDA in the event that additional testing is necessary. For example, FDA may need to repeat the bioavailability or bioequivalence testing or to perform other appropriate analyses such as content uniformity and dissolution testing on the samples.
The agency agrees that, for some reference standards, only limited quantities may be available in the marketplace. However, FDA believes that sufficient quantities are available to conduct the necessary "biostudies" and to provide the required reserve samples.
The agency continues to believe that the five times quantity standard is an appropriate standard for the reserve sample of the test article and of the reference standard and is retaining that standard in this final rule. However, a study sponsor or contract research organization may consult with the agency if it believes certain dosage forms present unreasonable storage problems. If a contract research organization is unsure of what quantity constitutes the five times quantity, it should contact the study sponsor.
15. One comment asked if the requirement to retain a sufficient quantity of reserve sample to allow FDA to perform five times all of the release tests required in the application or supplemental application provides enough sample for FDA to repeat the bioavailability or bioequivalence testing or perform other appropriate testing, if necessary. Another comment asked if the required retention sample size included sufficient material to allow for a so-called "split" sample so that the applicant could independently verify any tests conducted by the agency on the retained material.
The quantity of sample required to be retained is sufficient for all testing by FDA including a repeat of a bioavailability or bioequivalence study, if necessary. No additional samples beyond the five times quantity need be retained by the study sponsor or contract research organization. However, the required retention sample size does not provide sufficient material for independent testing by the study sponsor.
16. One comment asked for clarification of the sample retention requirement with respect to products that are manufactured in a dry form and [*25924] need to be reconstituted just prior to use in a study.
For purposes of the sample retention requirement in this rule, the reserve sample would consist of the product in the dry form, not the reconstituted form.
17. Two comments requested clarification of the effective date of the interim rule with respect to ongoing studies. One comment argued that testing programs already underway as of November 8, 1990, the effective date of the interim rule, should not have to be restarted because insufficient material is available to satisfy the sample retention requirement in addition to that necessary to conduct the required tests. The comment further stated that even if additional material from the same product lots were available, it could not be "representative" of the material submitted for the "biostudies" unless it had been submitted to the testing laboratory at the same time as the original material. One comment argued that, at a minimum, the new requirements should be deemed to be satisfied, in the case of ongoing studies, by the retention of as much material as is available after the testing is complete. This would also apply to study programs which commenced prior to November 8, 1990, if subsequent studies were planned to use the same limited lots of test or reference drugs.
The requirements established in the interim rule apply only to bioavailability and bioequivalence studies that were initiated on or after November 8, 1990.
18. One comment addressed the provisions of §§ 314.125(b)(17) and 314.150(b)(9), which state that FDA may refuse to approve, or to withdraw approval of, an application if an applicant or contract research organization refuses to permit an inspection of its facilities or records, or refuses to submit to FDA reserve samples when requested. The comment asked that when a contract research organization, without the knowledge or approval of the applicant, refuses to permit an FDA inspection of facilities or records relevant to a study or to submit to FDA reserve samples of drug products used in the study, the rule provide for notification to the applicant with an opportunity to intervene before any agency action to refuse to approve, or to withdraw the approval of, an application.
The agency advises that the regulations concerning FDA's action to refuse to approve an application or to withdraw the approval of an application are set forth under §§ 314.120 and 314.150, respectively. Thus, an applicant will have an opportunity to respond to any agency action by the procedures for denying or withdrawing the approval of an application. The agency emphasizes that, because actions or inactions of a contract research organization may affect the status of an applicant's application, the applicant may well wish to assure that the obligation to permit inspection and to release or submit to FDA reserve samples is included in any contract.
19. One comment suggested that the written assurance that the reserve samples came from the same samples as used in the specific bioavailability or bioequivalence study required under § 320.32(e) of the interim rule be modeled after 21 CFR 10.20(i), which requires that submissions to the Dockets Management Branch include a statement that, to the best of the knowledge, information, and belief of the person making the submission, the statements made in the submission are true and accurate. The comment argued that due to the extended period of time that samples must be retained and potential personnel turnover during that time, the person executing the written assurance may not have firsthand knowledge of the history of the sample being released to the agency, and may have to rely on company documentation. The comment further argued that an assurance provided under the interim rule would subject an individual to potential criminal liability under 18 U.S.C. 1001, based upon whether the statement is true or not, even though the person may not have direct personal knowledge of its falsity. Another comment asked in what form the written assurance should be. One comment asserted that both the sponsor and testing laboratory should certify that the reserve samples are those used in the specific bioavailability or bioequivalence studies submitted to FDA, and that copies of the certification statements should be held by both parties and be made available to FDA upon request.
The agency agrees that the person executing the written assurance may not have firsthand knowledge of the history of the samples and may have to rely on records of the applicant or contract research organization. Therefore, FDA has revised § 320.38(g) (§ 320.32(e) in the interim rule) to require that the applicant or contract research organization provide a written assurance that, to the best knowledge and belief of the individual executing the assurance, the reserve samples came from the same samples as used in the specific bioavailability or bioequivalence study identified by the agency. The written assurance may be in the form of a certification or other appropriate form. Because it is the contract research organization that separates out the reserve samples from the supplies of the test article and reference standard provided by the study sponsor rather than the study sponsor, FDA does not believe that the study sponsor can assure that the reserve samples came from the same batch as used in a specific bioavailability or bioequivalence study. Therefore, FDA does not agree with the assertion that both the study sponsor and testing laboratory certify with respect to the reserve sample.
20. Two comments asked that the requirement in § 320.32(b) of the interim rule, which requires that samples be positively identified as having come from the same sample as used in the specific bioavailability or bioequivalence study, be more specific as to what is expected.
The agency believes that specific ways to identify reserve samples and the study in which they were used should be left to the study sponsor or contract research organization responsible for retaining the samples. Therefore, the agency declines to provide specificity in the regulation. Appropriate identification may, however, consist of, but not be limited to, including on the sample container and in the study report, the product name, lot number, and study number.
21. One comment suggested that for inhalants that require exhaustive number of dosage units to be tested for release and require large storage space, a definitive number of retention samples, for example, 10 to 20 units, should be sufficient.
As discussed in section II.C.14, FDA does not intend to perform release testing on the reserve samples. Nevertheless, the agency does not agree that 10 to 20 units of an inhalant dosage form are sufficient for FDA's analysis and testing. As also discussed in section II.C.14, the reserve samples ordinarily will be used by FDA to perform a chemical and physical examination of the samples. The agency may also need to perform analyses such as content uniformity and dissolution for solid oral dosage forms and may need to repeat the bioavailability or bioequivalence testing. The agency concludes that the quantity of the reserve sample of an inhalant test article and of the reference standard needed for testing and analyses must be at least 50 units.
22. In the preamble to the interim rule, FDA stated it was considering whether additional requirements were [*25925] necessary to ensure the integrity of the reserve samples and invited comment on questions relating to storage area, need for a sample custodian, and packaging of the reserve samples. Seventeen comments responded to the agency's questions or otherwise addressed the issue of the need for additional requirements.
Two comments recommended that, under CGMP regulations, applicants be required to adopt written procedures for selection of samples from drug lots used in bioavailability or bioequivalence testing and for secure transmission of these samples to internal facilities or contract research organizations for "biotesting" and storage. Additional written procedures should establish the security measures to be followed for retained samples, including requirements for the storage area, sample custodian, and packaging of the samples to ensure that sample integrity is not compromised. Most of the comments recommended that the reserve samples be stored in an area where access is controlled and that is separate from the testing area. One comment, however, asked for a clarification of the wording "separate from" arguing that it is not necessary to require separation from the testing area so long as the storage area is segregated and access is controlled. A majority of the comments suggested that the need for a sample custodian should be left up to the applicant or testing facility and not be required by regulation. Responses to the questions of how the reserve samples should be packaged during the retention period to ensure that sample integrity is not compromised and to prevent tampering varied among the responders. Some comments recommended that the packaging of the reserve samples be in the same container/closure as that provided to the testing facility or a normal marketed package; other comments suggested using tamper-resistant packaging, using a sealed protective container such as glass, taking appropriate measures to prevent tampering, or that there is no need for specific packaging requirements if there is appropriate documentation based on written operating procedures.
FDA agrees with those comments recommending that reserve samples be stored in an area separate from the testing area and with controlled access. Accordingly, § 320.38(e) (§ 320.32(c) in the interim rule) has been revised to require that each reserve sample be stored in an area segregated from the area where testing is conducted and with access limited to authorized personnel. The agency has used the phrase "segregated from" rather than "separate from" because it is not intended that the storage area necessarily be in a different room, building, or facility. The requirement is intended to ensure that enough physical separation be employed by the study sponsor or contract research organization as is necessary to ensure that the integrity of the reserve sample is not compromised during the retention period.
The agency is not including other additional requirements at this time. If, based on FDA's inspectional experience and collection of reserve samples, the agency believes additional requirements are needed to ensure the integrity of the samples, it will propose appropriate revisions to this rule. The rule does not preclude study sponsors from adopting written procedures for the selection and transmission to the testing facility or contract research organization of the test article and reference standard for testing and storage of the reserve samples.
23. One comment noted that the interim rule did not address the situation where a contract testing laboratory goes out of business or is otherwise not in a position to continue to meet its obligations under the rule. The comment suggested that, under such circumstances, the sponsor should be allowed to recover from the contractor any retained samples from the studies it sponsored because sponsors are already required under the interim rule to maintain samples for studies conducted in-house. This would obviate the need for special procedures to deal with the insolvency of contractors or other potential problems with third party custodians, and would greatly simplify FDA's ability to obtain the samples because they would be readily available from the sponsor even for studies conducted by contract testing laboratories in foreign countries.
The agency agrees that the rule should provide for the transfer of reserve samples if a contract research organization goes out of business, but does not agree that the samples should be transferred to the sponsor or applicant for whom the contract research organization conducted the bioavailability or bioequivalence study. Rather, to preclude the possibility for sample substitution by a study sponsor or to preclude a study sponsor from altering a reserve sample, FDA concludes that the reserve samples should be transferred to an appropriate, independent third party, e.g., a commercial storage facility or a university. Therefore, a new paragraph (i) is added to § 320.38 (§ 320.32 in the interim rule), which states that when a contract research organization conducting a bioavailability or bioequivalence study requiring reserve sample retention goes out of business, it shall transfer its reserve samples to an appropriate, independent third party and shall notify in writing the sponsor of the study and provide the sponsor with the name and address of the facility to which the reserve samples have been transferred. Because the comment did not describe the circumstances in which a contract research organization "is otherwise not in a position to continue to meet its obligations under the rule," no further revision of the rule has been made.
24. One comment suggested that after the retention period is up, samples should be returned to the sponsor for proper accountability and destruction as required under CGMP's.
The agency advises that this final rule, like the interim rule, does not preclude such an approach. The study sponsor may wish to include in the contractual agreement with the contract research organization provisions for handling of the reserve samples after the retention period has expired. It should be noted, however, that the CGMP regulations do not address disposition of outdated reserve samples required to be retained under those regulations.
25. One comment suggested using a standardized photographic archiving procedure to show the drug product at the time of dosing for the bioavailability or bioequivalence study. This photographic record could be retained beyond the expiration date of the product, and would demonstrate the product's physical appearance.
The agency does not intend to require a photographic archiving procedure in this final rule; however, this does not preclude a testing facility from adopting such a procedure. FDA intends, as part of its physical analysis of a product that is a solid oral dosage form, to photograph each strength of each product to clearly document its shape, color, and distinctive markings. These photographs will be retained by FDA for later use in comparing subsequent batches of the test article or in comparing the test article to the reference standard.
26. Several comments addressed a statement in the preamble to the interim rule that states "in vitro and animal in vivo bioequivalence and bioavailability studies are within the scope of the good laboratory practice regulations." The comments argued that animal bioequivalence and bioavailability studies have not previously been [*25926] considered within the scope of 21 CFR part 58 except when conducted as part of a toxicology protocol or when conducted to directly support a toxicology protocol. The comments asked that FDA further clarify the scope of the preamble statement and this rule.
The agency believes the regulations at 21 CFR part 58 are ambiguous with respect to in vitro and animal in vivo bioavailability and bioequivalence studies required for approval of an NDA or ANDA; however, it is understood that no one considers those regulations to apply to the types of studies subject to this rule. Therefore, the requirements of this rule do not affect the reserve sample retention requirements under 21 CFR part 58.
FDA has examined the economic consequences of the changes implemented by the final rule in accordance with Executive Order 12291 and the Regulatory Flexibility Act (Pub. L. 96-354). This final rule more clearly defines the types of in vivo bioavailability studies for which reserve samples are to be retained. Although this rule has been in place as an interim regulation, the agency is not aware that it has imposed any undue costs. Nevertheless, because several comments to the record alluded to potential costs, the agency has conducted a Threshold Assessment of the final rule, which is on file with the Dockets Management Branch (HFA-305), rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.
The agency's assessment presents costs of retaining samples for an estimated 360 marketing applications per year. The study addressees both the additional storage costs and the acquisition costs of the test articles and reference standards. Storage costs were estimated on the basis of each sample requiring 0.5 square feet of storage for 5 years, and amounted to about $ 2,800. These costs would be roughly proportionate to the duration of the retention period. Acquisition costs of about $ 94,000 for reference samples were obtained from a survey of average retail prices of 16 well-prescribed medicines. Although individual circumstances may arise where storage or acquisition costs for a particular sample could rise substantially above these estimates, the agency believes that, on average, the annual costs of this rule will be about $ 100,000. FDA believes that these costs will likely be more than offset by the societal benefits of this rule, i.e., the added assurance that FDA's drug approval process functions effectively to ensure that only safe and effective drug products enter the marketplace. Accordingly, the agency concludes that this final rule is not a major rule as defined by Executive Order 12291, and certifies that the final rule will not have a significant impact on a substantial number of small entities, as defined by the Regulatory Flexibility Act.
(3) Any information on the incremental benefits of either retaining greater quantities of samples, or of retaining samples for greater periods of time.
Interested persons may, on or before May 28, 1993 submit to the Dockets Management Branch (address above) information on these areas. Two copies of any information should be submitted, except that individuals may submit one copy. Information submitted is to be identified with the docket number found in brackets in the heading of this document. Information received may be seen in the office above between 9 a.m. and 4 p.m., Monday through Friday.
Administrative practice and procedure, Confidential business information, Drugs, Reporting and recordkeeping requirements.
Drugs, Reporting and recordkeeping requirements.
§ 312.57 -- Recordkeeping and record retention.
(c) A sponsor shall retain reserve samples of any test article and reference standard identified in, and used in any of the bioequivalence or bioavailability studies described in, § 320.38 or § 320.63 of this chapter, and release the reserve samples to FDA upon request, in accordance with, and for the period specified in § 320.38.
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701, 706 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 371, 376).
§ 314.125 -- Refusal to approve an application or abbreviated antibiotic application.
(17) The applicant or contract research organization that conducted a bioavailability or bioequivalence study described in § 320.38 or § 320.63 of this chapter that is contained in the application or abb reviated antibiotic application refuses to permit an inspection of facilities or records relevant to the study by a properly authorized officer or employee of the Department of Health and Human Services or refuses to submit reserve samples of the drug products used in the study when requested by FDA.
§ 314.127 -- Refusal to approve an abbreviated new drug application.
(b) FDA may refuse to approve an abbreviated application for a new drug if the applicant or contract research organization that conducted a bioavailability or bioequivalence study described in § 320.63 of this chapter that is contained in the abbreviated new drug application refuses to permit an inspection of facilities or records relevant to the study by a properly authorized officer of employee of the Department of Health and Human Services or refuses to submit reserve samples of the drug products used in the study when requested by FDA.
§ 314.150 -- Withdrawal of approval of an application or abbreviated application.
(9) That the applicant or contract research organization that conducted a bioavailability or bioequivalence study described in § 320.38 or § 320.63 of this chapter that is contained in the application or abbreviated application refuses to permit an inspection of facilities or records relevant to the study by a properly authorized officer or employee of the Department of Health and Human Services or refuses to submit reserve samples of the drug products used in the study when requested by FDA.
Authority: Secs. 201, 501, 502, 505, 507, 701 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 355, 357, 371).
§ 320.31 -- Applicability of requirements regarding an "Investigational New Drug Application."
(c) The provisions of parts 50, 56, and 312 of this chapter are applicable to any bioavailability or bioequivalence study in humans conducted under an IND.
(2) An in vivo bioavailability or bioequivalence study in humans shall be conducted in compliance with the requirements for institutional review set forth in part 56 of this chapter, and informed consent set forth in part 50 of this chapter.
§ 320.38 -- Retention of bioavailability samples.
(a) The applicant of an application or supplemental application submitted under section 505 or 507 of the Federal Food, Drug, and Cosmetic Act, or, if bioavailability testing was performed under contract, the contract research organization shall retain an appropriately identified reserve sample of the drug product for which the applicant is seeking approval (test article) and of the reference standard used to perform an in vivo bioavailability study in accordance with and for the studies described in paragraph (b) of this section that is representative of each sample of the test article and reference standard provided by the applicant for the testing.
(1) If the formulation of the test article is the same as the formulation(s) used in the clinical studies demonstrating substantial evidence of safety and effectiveness for the test article's claimed indications, a reserve sample of the test article used to conduct an in vivo bioavailability study comparing the test article to a reference oral solution, suspension, or injection.
(2) If the formulation of the test article differs from the formulation(s) used in the clinical studies demonstrating substantial evidence of safety and effectiveness for the test article's claimed indications, a reserve sample of the test article and of the reference standard used to conduct an in vivo bioequivalence study comparing the test article to the formulation(s) (reference standard) used in the clinical studies.
(3) For a new formulation, new dosage form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved for marketing, a reserve sample of the test article and of the reference standard used to conduct an in vivo bioequivalence study comparing the test article to a marketed product (reference standard) that contains the same active drug ingredient or therapeutic moiety.
(c) Each reserve sample shall consist of a sufficient quantity to permit FDA to perform five times all of the release tests required in the application or supplemental application.
(d) Each reserve sample shall be adequately identified so that the reserve sample can be positively identified as having come from the same sample as used in the specific bioavailability study.
(e) Each reserve sample shall be stored under conditions consistent with product labeling and in an area segregated from the area where testing is conducted and with access limited to authorized personnel. Each reserve sample shall be retained for a period of at least 5 years following the date on which the application or supplemental application is approved, or, if such application or supplemental application is not approved, at least 5 years following the date of completion of the bioavailability study in which the sample from which the reserve sample was obtained was used.
(f) Authorized FDA personnel will ordinarily collect reserve samples directly from the applicant or contract research organization at the storage site during a preapproval inspection. If authorized FDA personnel are unable to collect samples, FDA may require the applicant or contract research organization to submit the reserve samples to the place identified in the agency's request. If FDA has not collected or requested delivery of a reserve sample, or if FDA has not collected or requested delivery of any portion of a reserve sample, the applicant or contract research organization shall retain the sample or remaining sample for the 5-year period specified in paragraph (e) of this section.
(h) A contract research organization may contract with an appropriate, independent third party to provide storage of reserve samples provided that the sponsor of the study has been notified in writing of the name and address of the facility at which the reserve samples will be stored.
(i) If a contract research organization conducting a bioavailability or bioequivalence study that requires reserve sample retention under this section or § 320.63 goes out of business, it shall transfer its reserve samples to an appropriate, independent third party, and shall notify in writing the sponsor of the study of the transfer and provide the study sponsor with the name and address of the facility to which the reserve samples have been transferred.
§ 320.63 -- Retention of bioequivalence samples.
The applicant of an abbreviated application or a supplemental application submitted under section 505 or 507 of the Federal Food, Drug, and Cosmetic Act, or, if bioequivalence testing was performed under contract, the contract research organization shall retain reserve samples of any test article and reference standard used in conducting an in vivo or in vitro bioequivalence study required for approval of the abbreviated application or supplemental application. The applicant or contract research organization shall retain the reserve samples in accordance with, and for the period specified in, § 320.38 and shall release the reserve samples to FDA upon request in accordance with § 320.38.

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