The birth

MINISYMPOSIUM

of a new radiopharmaceutical

Several new radiopharmaceuticals for myocardial perfusion imaging have been approved for clinical use in recent years or are presently undergoing clinical testing. The time, effort, and cost involved in the entire process of development of a radiopharmaceutical, from initial conception to final approval for clinical use, is enormous. The following series of articles, which use 99mTc-labeled sestamibi as an example, is meant to clarify and to provide better insight into the various stages of the entire process of development and approval.

The perspective of the Food and Drug Administration (FDA) on the development of a new radiophar- maceutical is given by David H. Woodbury, MD, Medical Officer at the FDA. B. Leonard Holman, MD, and Alun G. Jones, PhD, of the Brigham and Women's Hospital and Harvard Medical School, describe the process of initial clinical development and experience with various compounds of the 99mTc-labeled isonitrile class, which led to the development sestamibi. The long and circuitous route of the industrial and commercial development of and new drug application (NDA) of sestamibi is described by Linda P. Giering, PhD, and James E. Smith, PhD, of DuPont Pharma. Frans J. Th. Wackers, MD, of Yale University presents the point of view of a clinical investigator involved in phase I, II, and III clinical trials.

Frans J. Th. Wackers, )kiD Associate Editor

Food and Drug Administration involvement and approval

D a v i d H. W o o d b u r y , M D

A new drug may not be commercially marketed in the United States, imported, or exported from the United States, unless it has been approved as safe and effective by the Food and Drug Administration. Such approval is based on a New Drug Application (NDA) (21 CFR 314) submitted by the sponsor of the drug, containing acceptable scientific data including results of tests to evaluate its safety, and substantial evidence of effectiveness for the conditions for which the drug is to be offered?

This article will (1) summarize the historical background leading to current regulations, (2) discuss those elements of an investigational new drug (IND) that lead to a new drug application (NDA), and (3) discuss those elements of the NDA that may be unique for radiopharmaceuticals.

Historical Perspective

In the first session of the 59th Congress, June 30, 1906, President Theodore Roosevelt signed into law

Reprint requests: David H. Woodbury, MD, Medical Officer, Federal Drug Administration, 5600 Fishers Ln., Park Lane Bldg HFTD 160, Rockville, MD 20857.

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the first federal food and drug law. The passage of the 1906 law gave the Food and Drug Administration (FDA) authority to remove from the marketplace drugs that they could prove were not pure or that were unsafe.

Since enactment of the 1906 act, amendments have been promulgated to improve the act and strengthen the authority of the FDA in the regulation of food, drug, and cosmetic products marketed for human use. They include: The Sherley Amendment - 1912, prohibited false statements about the identity of drug products.

The Copeland Amendment-1938, placed greater emphasis on safety by requiring applicants to provide evidence of drug safety before marketing; to provide toxicity studies, develop product labeling that sum- marizes dosage, indications of use, chemical class, and structure.

The Kefauver-Harris Amendments-1962, re- quired that extensive pharmacologic and toxicologic research be submitted to the FDA before human test- ing. 2 With these amendments, the introduction of a new drug into humans by any means requires an exemption from the Food Drug and Cosmetic Act (FDandC) to allow experimental studies through the

JOURNAL OF NUCLEAR CARDIOLOGY Woodbury 63 Volume 2, Number 1;62-65 Food and Drug Administration involvement and approval

filing of an application for an investigational new drug (IND). The IND usually contains a description of three progressive phases of clinical studies before submission of a new drug application (NDA) for mar- keting. The NDA submission is required to demon- strate substantial evidence of safety and effectiveness through "adequate and well controlled studies. ''3

In addition to clinical data supporting safety and effective performance, the NDA requires inclusion of records and reports detailing manufacturing, drug quality, pharmacology, statistical analysis, and strengthening of prescription drug advertising re- quirements. The important change with the new amendments is that the clinical phases of a study provide data and an analysis of data to prove efficacy of the product.

The current regulatory dicta for IND/NDA sub- missions are found in the Code of Federal Regula- tions (CFR)21, part 312.20 through 312.70, and parts 314.50 through 314.170, respectively. Radiopbarma- ceuticals, whether indicated for diagnostic or thera- peutic purposes, differ significantly from most drugs used for therapy. The differences include frequency of use, pharmacologic response, pharmacokinetics, and pharmacodynamics. In the following description of the process of approval of new radiopharmaceuti- cal drugs, particular attention will be made to those unique aspects of radiopharmaceuticals that must be considered in the FDA review.

The Review Process

IND and NDA radiopharmaceutical submissions to the FDA are reviewed by four disciplines: phar- macology, chemistry, biostatistics (usually PhDs), and medicine (clinical specialist Board certified in nuclear medicine). For an IND, a reviewer from each discipline summarizes the data submitted pertaining to that specialty; completes and forwards a report, with recommendation to disapprove, approve without modification, or approve with modification to the section group leader (a senior officer), who appends a brief note. The summaries, along with the original submission are forwarded to the division director. After review of the submited reports, a section meeting is held with the division director to discuss and resolve any conflicting recommendations. Typi- cally at this meeting decisions are made to approve the IND for investigative studies or to place on "clinical hold" pending clarification of ambiguities or requests for additional data. By law, response to an IND application must be completed in 30 days, or the investigator(s) may initiate the study.

NDA submissions are more extensive than are INDs; these submissions collate all the nonclinical and clinical data derived from all phases of the

investigative trials to validate in "adequate and well controlled studies" at two or more independent sites that the new radiopharmaceutical is safe and effective. The NDA submission is reviewed by all the disciplines previously listed, with consultation from other disci- plines as needed (i.e., biopharmacy, oncology).

After completion of all reviews of tbe NDA, several sectional meetings are held: (1) meetings to review the precise language to be included in the package insert, (2) meeting with the Advisory Com- mittee (two times per year) to discuss the overall NDA for their input and recommendations, (3) a final meeting with the deputy center director, division director, group leaders, and all reviewers to assess all aspects of safety and efficacy claims. At this meeting the decision is made as to whether the new drug entity is approved for marketing, approvable after correc- tion of minor deficiencies, or not approved. The signature of the deputy director of the Center for Drug Evaluation and Research in a letter of approval to the sponsor allows the sponsor to prepare for the marketing and clinical use of the new product.

From the date of the NDA receipt by the Division, action must be completed on drugs of high priority in 6 months; on drugs of standard priority in 12 months. Priority is established by the importance of the new drug in diagnosis or therapy.

In each phase of a review there are specific elements that are evaluated to assure meeting the legal mandates of Congress, as outlined in the Code of Federal Regulations. Those critical elements, and their CFR references, will be summarized herewith to assure completeness in understanding the review process.

Investigational New Drug Application. 21 CFR sec. 312.20. Before administration of a new drug into human beings there is the requirement that manufacturers submit data on investigational new drugs "describing the pharmacologic effects and mechanism(s) of action of the drug in animals, and information on the absorption, distribution; metabo- lism and excretion of the drug if known."

Dosimetry Review. Diagnostic radiopharma- ceuticals rarely elicit a detectable pharmacologic response. The usual studies of biodistribution and excretion in separate animal species are primarily designed to establish essential information for dosim- etry calculations. The desirable approach is to deter- mine the concentration of a radiopharmaceutical in all major organs and blood at selected times after injection of the drug. From these studies the organs receiving the highest radiation absorbed dose can be identified; blood to organ ratios can be developed; and for imaging purposes, target-to-nontarget con- centrations can be evaluated. It is helpful if the calculations used to determine estimated body/organs

64 Woodbury JOURNAL OF NUCLEAR CARDIOLOGY Food and Drug Administration involvement and approval January/February 1995

burdens are part of the submission under safety determinants.

Chemistry Review, CFR 21 sec.312.23(7), stipu- lates that " . . . sufficient information is required to be submitted to assure the proper identification, quality, purity and strength of the investigational drug." The documentation required for the chemistry, manufac- turing, and controls (CMC) section of an IND application should contain all pertinent information that demonstrates that the drug product can be prepared in sufficient quantity and purity to be safe for human administration. The essential elements of the CMC include description of the drug substance, drug product, quality controls, and container/closure.

NDA submissions follow the same format for documentation required for the CMC section. How- ever, there are differences in the extent of information required: an NDA will require greater emphasis on structure proofs, purity profiles, and quality controls for raw materials and finished drug product. Stability studies must support the assignment of the expiration date. Environmental impact assessment must be stipulated.

Biostatistics Evaluation, 21 CFR 314.126(a), states "The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect or biased observation." Statistical analysis of data submitted to substantiate the safety and efficacy of a new radiopharmaceutical drug product helps to validate claims made and verify the degree to which an hypothesis has been proven or disproven.

Clinical Reviews

IND Submissions, 21 CFR sec.312.22, states "FDA's primary objectives in reviewing an IND are, in all phases of the investigation, to assure the safety and rights of subjects, and, in Phases 2 and 3, help assure the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drugs effectiveness and safety." When designing the plan of investigation, the intended indication for the use of the new agent should be stated, and the clinical trial designed to gather data to support the intended use.

The IND review of a new radiopharmaceutical is divided into three phases, with some possible overlap in phases 2 and 3. The following outline summarizes those elements in each phase deemed essential for adequate evaluation.

Phase 1 includes the initial introduction of an investigational new drug in human beings. The overriding determinant in this phase is to validate

safety in human studies with the new drug. These studies should include half-time blood clearance data, normal biologic distribution of the radiopharmaceu- tical, maximum organ concentration of the radio- pharmaceutical, routes of excretion, and optimal times for sampling and imaging.

A small number of normal or diseased patients (5 to 10) is usually sufficient to obtain the necessary biodistribution biokinetic and metabolic data needed to develop radiation dosimetry values. Radiation dosimetry should account for all the assumptions made in the derivative calculations. (Dosimetry esti- mates may be validated in consultation with the Radiation Internal Dose Information Center, Oak Ridge, Tenn.).

Determination of the optimal dose range for a diagnostic radiopharmaceutical may be influenced by imaging time per view, the need for ample photons to provide adequate images, and the necessity to keep the absorbed dose as low as is practicable.

Appropriate clinical laboratory tests are required to record the response, if any, to administration of the new drug. These tests typically include chemistry profile, urinalysis, hematologic profile, electrocardio- grams, and any other tests deemed necessary after evaluation of the history and physical examination. These tests are usually performed before and at selected times after administration of the new drug.

Whereas diagnostic radiopharmaceuticals, cur- rently approved, affect no change in vital signs or biochemical parameters, tracers bound to other chemical ligands require stability validation of vital signs and biochemistry. Significant deviations from baseline, particularly changes that fall outside ac- cepted norms, must be detailed and fully evaluated.

Phases 2 and 3 protocols are designed to study that cohort of patients the new drug is to identify or treat, and may be comparator or placebo controlled with single, or preferably, double blind design. The objectives of the study must be succinctly stated and the rationale behind the protocol design explained. The demographics of the patient population, includ- ing gender, age, ethnic origin, and medical history are important elements of these protocols. Any signifi- cant variation noted in imaging response between sexes or ethnic groups should be noted.

Protocols for diagnostic radiopharmaceuticals differ from therapeutic protocols in the following ways: Evaluation of safety requires less detailed study of pharmacologic toxicity and is primarily related to estimation of absorbed radiation doses. A diagnostic radiopharmaceutical is considered effective if its use contributes to a decision as to the presence, absence, or extent of disease. An adequate number of patients

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are needed in each phase to meet required statistical determinants; depending on clarity of response, as few as 20 to 60 patients may suffice in phase 2 protocols, and 200 to 300 patients may provide adequate data for phase 3 studies, compared with the larger number needed for therapeutic evaluation.

One of the most critical requirements for phase 3 evaluations is the performance of the studies under a common protocol in at least two separate and independent institution sites and investigators. The separate studies validate the ability to replicate the safety and efficacy determinants of the new agent with the particular dosage form and for the proposed indication. The following outline, summarized from Guidelines for the Clinical Evaluation of Radiophar- maceutical Drugs 4 lists those elements that are com- mon to protocols of both phases and to all indepen- dent studies:

�9 The objective of the study should be clearly defined in short precise statements.

�9 The rationale for the study should include data that suggest the hypothesis that the new agent offers a unique diagnostic/therapeutic methodology.

�9 The criteria by which efficacy will be developed should be detailed.

�9 The experimental design should include admission and exclusion criteria, demography of patients enrolled, stratification of patients, description of instrumentation and techniques; the dose, in milli- grams or millicuries, to be administered and route of administration. The criteria by which efficacy will be established should be stated prospectively. Projected human radiation dosimetry should be shown.

�9 Case report forms (CRF) designed to record all the previously mentioned data, test results, vital signs, and all adverse events should be maintained for each subject in the study.

�9 Patient consent forms must be obtained for each patient. A copy of the proposed form should be submitted with the NDA.

After completion of the phase 3 clinical trials the manufacturer compiles the data and submits a New Drug Application (NDA).

NDA Submissions, 21 CFR 314.50, outlines the inclusions needed to meet the legal requirements of the New Drug Application for approval to market a new radiopharmaceutical. The NDA submission col- lates and summarizes all of the nonclinical and clinical data derived to validate the safety and efficacy of the drug product. Principal elements of the NDA (from 21 CFR 314.50(c) i-ix) include:

�9 summaries of the CMC section, nonclinical phar- macology and toxicology, human pharmacokinetics and biodistribution sections of the application;

�9 summaries of the clinical data section of the application, including the results of the statistical analysis of the clinical trials; and

�9 a concluding discussion that presents the benefit and risk considerations related to the drug.

Package Inser t . This document represents the final distillate of information that accompanies the NDA for review and approval. This document con- tains a summary of the essential scientific information needed for the safe and effective use of the drug. Whereas, the labeling information is to be accurate and informative, it cannot be promotional, mislead- ing, or false. All information included in this docu- ment should be based on proven human data that are presented in the NDA and are under a prescribed format that includes indication, usage, dosage, and administration, as well as warnings and adverse reactions noted in the clinical trials.

The foregoing summarizes those key elements, required by law, and needed by the FDA for review of IND/NDA submissions for new drug marketing. As in any summary of data some fine points may not be clear or adequately explained; to improve communi- cations between the FDA and the members of the nuclear medicine community, commercial sponsors, institutional and private investigators are encouraged to contact the FDA at any stage of drug development and clinical trials to discuss potential problems, design of clinical trials, and establishment of adequate statistical endpoints. It is hoped that the improved communication will help decrease the time required to review and bring to market new radiopharmaceu- ticals.

References

1. Requirements of laws and regulations enforced by the US Food and Drug Administration. Rockville, Maryland: Superin- tendent of Documents; 1989; DHHS publication no (FDA)89- 1115.

2. The staff of the U.S. House of Representatives Subcommittee on Public Health and Environment. A brief legislative history of the Food, Drug and Cosmetic Act. Washington: US Govern- ment Printing Office; 1974.

3. National Archives and Records Administration. Food and Drug Administration: 21 CFR part 312 Investigative new drug application, and part 314.126. Federal Register Special Edition. 1 1992 April; FDA 21: CFR312; 314-126.

4. Guidelines for the clinical evaluation of radiopharmaceutical drugs. Rockville, Maryland: US Department of Health and Human Services; 1981; 1981; HHS publication no 81-3120.