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Supporting pharmaceutical studies for FDA submissions: diversifying the drug monitoring laboratory.

There is a rigorous review process associated with bringing a new pharmaceutical product to the consumer market in the US. Introduction of a new drug or a new clinical application for a drug requires demonstration to the US Food and Drug Administration (FDA) that a beneficial effect can be clearly associated with that drug; side effects and toxicities must be declared with statements from medical experts, indicating that the clinical benefits outweigh any known detrimental effects; and the pharmacokinetics of the drug must be defined as technology allows. The process of filing with the FDA to obtain approval to market the drug is known as a New Drug Application (NDA). (1)

For generic drugs, the process of applying for approval to market is described as an Abbreviated New Drug Application (ANDA), "abbreviated" in that the application does not require information supporting the clinical efficacy because that has already been demonstrated. Information describing the pharmacokinetic characteristics of the proposed generic form of the drug must be submitted to document that the generic form is biologically equivalent to the proprietary product.

Laboratories involved in studies supporting an NDA or ANDA must perform their work in compliance with defined standards. The studies required to assess the health status of human subjects involved in studies must be carried out by laboratories certified or accredited in accordance with the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88), which is outlined in the US Code of Federal Regulations (CFR), Title 21 [1-3]. Those studies designed to demonstrate the pharmacodynamic properties of the drug must be carried out in accordance with good laboratory practice (GLP), which is outlined in the CFR Parts 58, 211, and 320 [1-3].

Laboratories providing therapeutic drug monitoring (TDM) services are uniquely situated for involvement in ANDA filings and, to a lesser extent, NDA filings. Personnel associated with TDM laboratories are knowledgeable about the physiological and analytical attributes needed to perform good pharmacokinetic evaluations, and TDM laboratories are appropriately equipped to respond to the rigorous analytical requirements.

TDM laboratories have been involved in pharmaceutical evaluations since their inception because there are considerable opportunities to do so. In the first 6 months of 1997, the following new drugs were approved by the FDA: Agrylin, Alesse, Anzemet, Carbatrol, Fareston, Flomax, Galzin, Idamycin, Migranal, Posicor, Prelay, Prevacid, Pytest, Requip, Resulin, Serlect, Skelid, Tasmar, Uniretic, Urso, Vicoprofen, Viracept, Zyban. During 1997 through 2000, the patents for 47 proprietary drugs are due to expire, and each of these is likely to be challenged by four to six generic equivalents. Assuming a similar trend in the subsequent few years, >600 pharmacodynamic studies will probably be carried out between 1997 and 2000 to support NDA or ANDA filings.

Here, we provide a general overview of the laboratory requirements to support the pharmacodynamic evaluation of new drugs for FDA filings. This document serves only to note key features of the laboratory process and is not intended to replace the details outlined in the CFR or in other pertinent publications [1-9]. Laboratories supporting such studies must be fully aware of the requirements outlined in the CFR [1-3].


The FDA is a regulatory agency of the US Government with broad authority over products intended for public consumption. Any food or drug product sold to US consumers comes under the purview of this regulatory body. FDA inspectors are law enforcement officers; their job is to ensure compliance with federal law. They have police powers, can make arrests, and are involved in obtaining evidence for federal prosecution. Failure to comply with published rules or intent to subvert those rules is a federal offense.


Private research facilities engaged in providing contract services are frequently referred to as contract research organizations. These agencies contract with pharmaceutical houses to carry out product evaluation, and often subcontract work directly to laboratories as part of that function. They provide a broad range of services, ranging from any one to all of the following:

1) Design study protocol.

2) Solicit investigators or function as a study site themselves.

3) Manage clinical supplies, drug administration, and sample collection, either on site or from a variety of distant sites.

4) Perform analytical studies.

5) Perform pharmacokinetic, pharmacological, and statistical evaluation.

6) Do field management (monitoring or auditing) of sites.

7) Prepare final document for submission to the FDA.

8) Manage storage of samples and records.


Laboratory-derived information included as part of an FDA filing that describes the product being evaluated must be collected in a laboratory setting that complies with the GLP regulations. These data are considered to be different from the data that document the health status of study subjects, which must be carried out by a certified or accredited clinical laboratory (CLIA). While both GLP and CLIA proscribe accuracy, quality, and precision, the kind of documentation and control of the data are very different. Part 58 of CFR 21 outlines the conditions to be met when performing studies under GLP standards. These standards apply to all studies of a drug, food additive, or classified medical device.

Each study must have an approved, written protocol, which must include title and statement of purpose, name and address of sponsor, definition of experimental design, documentation of dosages used, type and frequency of testing to be used, definition of records to be maintained, and a statement of proposed statistical methods. This protocol must be completed by notation of review by management and the Lab Study Director with date and signature.

The sites involved in the study--whether investigator sites, where patients are seen, or test facilities, where analytical functions are performed--must have written Standard Operating Procedures (SOPs) defining how to perform each operation that can affect study performance or the integrity of the data gathered. There must be written documentation of the organizational outline and personnel, with records of their qualifications on file. Testing equipment, including computers and the applications on them, must be governed by SOPs. Computing and data management systems must be fully validated and under strict change control. A quality assurance function must be fully described and active. In the event of an inspection, whether sponsor-initiated or FDA-initiated, the quality assurance unit would be expected to be a chief contact for the inspection team.

The site must have a person who is held primarily responsible for technical conduct of work performed there. Usually called a Study Director, he/she must be a scientist or professional with appropriate education, training, and experience to approve technical SOPs; assures that studies are carried out according to the protocol and that SOPs are followed; assures that data are accurately recorded and that all data, reports, and specimens are stored according to protocol; and defines corrective action for unforeseen events.

The quality assurance unit at the site is responsible for monitoring the conduct of the study. The person who carries out quality assessment must report to management and be independent of the Lab Study Director. This person assures, on a regular basis, that the study was performed in accordance with SOPs and prepares a written and signed final report indicating that the study was carried out according to protocol, noting and explaining any deviation from protocol observed.

Facilities must be suitable in size and construction to facilitate proper conduct of study. Clinical trials work often requires a separate laboratory space to ensure a degree of separation from other activities--to prevent other functions from having an adverse effect on the study and to provide for uniform, consistent handling of raw data, specimens, and copies of all SOPs. Consider also that batch analysis of specimens is often preferred so that a pharmacokinetic series within a patient is analyzed in the same run. This may require more setup space than is commonly available. Although key-controlled access is not required, some measure of increased security is required to ensure that study documents are not readily available to personnel not involved in the study activities. At a minimum, locked cabinets and document-control procedures are needed.

Equipment records for clinical trial work are similar to those required under CLIA standards. Laboratories should review their storage and retrieval procedures for such records because an inspection may occur some years after the actual work, and it is important to be able to unequivocally link the instrument maintenance records with the actual time during which the study work was being performed.

SOPs are the heart of the laboratory's documentation of their work. To the FDA inspector, just as to the CLIA inspector, they define how you intend to do a task. An inspector will first evaluate whether the SOPs are adequate and then judge your work against your own standards. In general, analytical SOPs written according to NCCLS guidelines meet the expectations of any clinical trial work. However, the site must also have SOPs for all critical pre- and postanalytical functions, and those SOPs are subject to the same periodic review and approval requirements as the analytical SOPs. The site must also have SOPs that define the action to be taken when deviations to SOPs occur.


The laboratory methods used to support pharmaceutical studies must be appropriate for the purpose of the study. Selection of methodologies, whether they be immunoassay, HPLC, GC/MS, HPLC-MS, or any variation of these, is dictated by the study protocol. Validation of analytical performance is a key requirement. Specific points to address during validation include:

1) Check the lower limit of quantitation (LOQ). A drug that is slowly cleared may have to be measured for longer times and at very low concentrations to obtain all the pharmacokinetic data needed to show equivalence.

2) Metabolites may need to be measured, even if they are not pharmacologically active, to document the metabolic profile of the drug in the appropriate clinical populations. It is important to study patients with impaired organ function, especially in renal disease, to determine the effects of their condition on clearance of the drug.

3) Full pharmacokinetic data for an NDA usually requires that urine concentrations for parent and metabolites be determined.

4) To determine toxicity thresholds, peak drug concentrations considerably greater than therapeutic values are often reached, so the upper limit of linearity of an assay may need to be extended.

Validation of analytical procedures is required but is not outlined in the CFR. The proceedings of a consensus conference [8] and a paper by Kames et al. [9] set the precedent for validation of procedures.

Testing facilitates must investigate each step in a procedure to determine the impact that each matrix, material, or procedure variable has on the final result. Wherever possible, the same biological matrix as the study sample should be used. The stability of each analyte in the study matrix under the collection and storage conditions used should be documented for the duration of the study. Stability studies over three storage (freeze-thaw) cycles are recommended. Also recommended is carrying out method validation with samples from dosed subjects. The precision, recovery, response function, and specificity (with regard to metabolites, known degradation products, expected concomitant medications, and known endogenous substances) of each method should be defined by evaluating the procedure with six or more samples. A simple, statistically testable response function to be recorded graphically must be defined for implementation by the quality assurance SOP.

Proof of accuracy is required. This can be accomplished by comparison with reference procedures or defined, previously validated methods. Use of absorptivity values to verify the accuracy of stock standard preparations is appropriate. Replicate sets of samples containing known concentrations of the analyte (when available) should be assayed as further evidence of accuracy.

Use of five to eight calibrators is recommended to define the standard curve. Linear regression is preferred, but weighting factors to improve precision are acceptable. Precision must be defined by using replicate analysis at three concentrations, to span the range from the LOQ to the upper limit of linearity. The method should demonstrate precision, with the CV not to exceed 15% except at the LOQ, where it should be defined by assaying five replicates and should not exceed 20%.

Test controls must be defined that declare how reagents will be characterized in terms of identity, strength, purity, and composition. Methods must define how reagent stability will be demonstrated. Reagents must be characterized before the study is initiated, and periodic characterization is required as defined in protocol. For studies of >4 weeks' duration, reserve samples of all reagents must be retained.

If stereoisomeric measurements are made, each method must be validated. Stereoisomeric measurements are not required for existing racemic products. For new products with racemic activity, however, stereoisomeric measurements should be made.

In conclusion, laboratories currently engaged in a TDM clinical practice are familiar with all of the concepts outlined above and fully capable of participating in the evaluation of new pharmaceutical products. Successful participation requires thorough knowledge of the requirements for filing with the FDA, careful documentation of all processes, and understanding that retrospective review of data is likely to occur. Data management and retrievable, intact, complete records are key elements in this process.

Received August 11, 1997; revision accepted November 21, 1997.


[1.] Good laboratory practice for nonclinical laboratory studies. Title 21, Code Fed Reg 1994;58:245-59.

[2.] Current good manufacturing practice for finished pharmaceuticals--laboratory controls. Title 21, Code Fed Reg 1004;211(160): 93-9.

[3.] Bioavailability and bioequivalence requirements. Title 21, Code Fed Reg 1994;320:178-93.

[4.] CDRH. Medical device good manufacturing practices manual, 5th ed. 91-4179. Washington, DC: FDA, 1991.

[5.] Compliance policy guide, FDA access to results of quality assurance program audits and inspections, 7151.02. Washington, DC: FDA, 1989.

[6.] Guide to inspections of pharmaceutical quality control laboratories. Washington, DC: FDA, July 1993.

[7.] Davis RJ. A guide to inspection of pharmaceutical quality control laboratories. Pharm Eng 1992;Sept/Oct:36-42.

[8.] Shah VP, Midha KK, Dighe S, McGilveray IJ, Skelly JP, Yacobi A, et al. Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Conference Report. Pharm Res 1992;9:588-92.

[9.] Karnes HT, Shiu G, Shah VP. Validation of bioanalytical methods. Pharm Res 1991;8:421-6.


Department of Laboratory Medicine and Pathology, H-400 Mayo Clinic, Rochester, MN 55905.

* Author for correspondence.

Abstract presented at the AACC annual meeting, July 22,1997: Clin Chem 1997;43(Suppl):SS5.

(1) Nonstandard abbreviations: NDA, New Drug Application; ANDA, Abbreviated New Drug Application; CFR, Code of Federal Regulations; GLP, Good Laboratory Practice; LOQ, limit of quantitation; and SOP, standard operating procedure.
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Title Annotation:TDM Conference
Author:Moyer, Thomas P.; Oliver, Lawrence K.
Publication:Clinical Chemistry
Date:Feb 1, 1998
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