To gain FDA approval or license for marketing, a pharmaceutical product must be shown to be safe and effective for its proposed or intended use. The drug company or sponsor must also provide evidence to show that the processes and control procedures used for synthesis, manufacture, and packaging are independently validated to ensure that the pharmaceutical product meets established standards of quality. The overall effort from the inception of a new molecular entity and the establishment of analytical, scale-up, and quality control procedures, to the collection of safety and efficacy data for consideration by the FDA as part of an NDA or BLA, is called the drug development process.
While the journey from the discovery of a drug candidate to final marketing approval can be lengthy, the steps are well defined for both traditional drugs and bio-pharmaceuticals. Figure 2.1 is a schematic presentation showing that after chemical or biological synthesis and purification, the NME is rigorously and systematically evaluated in preclinical studies that include the characterization of its physical-chemical and biologic properties, the determination of its toxicity in laboratory animals and cell systems (gross toxicity, hematological and end-organ effects, carcinogenicity, mutagenicity, and teratogenicity), the establishment of its distribution and phar-macokinetic profile in laboratory animals, and the evaluation of its stability and other characteristics important to the preparation of a final dosage form.
Before animal testing, analytical and biological assay capabilities must be developed while the NME is being scaled up to produce a sufficient quantity with acceptable purity for use in subsequent studies. Drug standards and analytical methods for evaluating the bulk NME and the final product, as well as the tentative chemical, physical, and biologic specifications, are then established. In parallel, formulation studies are initiated to produce a stable dosage form that will provide a suitable platform for delivery of the NME in a reproducible manner.
Often a series of related NMEs with similar chemical structures are evaluated systematically to optimize specificity and affinity to the target molecule or cellular receptor and minimize potential drug-drug interactions by selection of molecules with a low affinity for key drug metabolizing enzymes. Those candidates with desirable in vitro profiles are evaluated further in laboratory animals for pharmaceutical properties that include good target bioavailability (adequate absorption after administration and an ease of distribution or transport to the site of action) and a degree of resistance to metabolism and excretion to ensure that the drug molecule
persists for a sufficient time at the site of action; these are often called absorption-distribution-metabolism-excretion (ADME) studies. The studies designed to characterize pharmaceutical properties are important in drug development to predict whether a pharmacologically active compound will be useful as a therapeutic agent. Preclinical studies must also establish the range of doses needed to produce pharmacological and toxicological responses in commonly used animal models and characterize those responses at the organ, cellular, and molecular levels.
A drug candidate that completes pre-clinical testing and maintains promise is then considered for evaluation in human subjects. The first step in this process is the
Investigational New Drug (IND) application. The IND petition requires full disclosure of where and how the NME is manufactured and controlled for quality and stability. It also contains proposed analytical methods, pharmacology and toxicology data, and evidence of desired effects in disease models. The application lists proposed clinical investigators and contains complete human subject protocols. Under current regulations the FDA must provide a written response to the sponsor within 30 days after submission. The lack of a timely response is tacit approval for the sponsor to proceed to the clinic.
The NME can now be administered to humans. The first step in clinical evaluation is one or more phase I studies designed to assess the drug's safety and pharmacokinetic profile. Phase I studies usually involve a small number of healthy volunteers who are closely monitored after receiving escalating doses of the drug candidate. Phase I studies of drugs for cancer or HIV infection must be carried out in patients, not in healthy subjects. Ordinarily, until more information is available, the minimum dose to induce side effects is stipulated as the upper dose limit for subsequent administration to human subjects.
The efficacy of new drug candidates with acceptable safety profiles—based on phase I findings—is evaluated in phase II studies in patients with medical disorders consistent with the sponsor's proposed indication (s). Mindful of getting its drug candidate to market as quickly as possible, drug sponsors usually select patients with well-defined medical conditions and use surrogate end points to evaluate response. A sponsor may seek a very narrow indication to expedite evaluation, with the hope of expanding that indication for a larger patient population based on studies carried out after initial approval and marketing. Phase II clinical studies enroll several hundred subjects and are designed not only to assess efficacy but also to detect acute and short-term side effects and risks asso ciated with the investigational drug. Some phase II studies are well controlled, while others are open.
A new drug candidate that successfully completes phase II studies, safely demonstrating benefit in a well-defined patient population, is then required to undergo additional clinical testing (phase III) in designated patients, usually under rigorously controlled conditions, to collect sufficient data to evaluate the drug's effectiveness and safety with regard to an overall assessment of the benefit-risk relationship. Phase III clinical trials often involve multiple medical centers and enroll several hundred to several thousand subjects.The exact number of subjects required for phase II and phase III studies depends primarily on statistical considerations that take into account the expected differences in therapeutic end points for active drug and placebo, the patient population, and the expected variation in biotherapeutic assessment.
When phase III studies near conclusion, nonclinical and clinical data are assembled for submission to the FDA in an NDA or BLA. The staff at the FDA and members of FDA advisory committees, which are composed of experts in a therapeutic area, review the application and attempt to ensure that the benefits of the new drug outweigh its risks.
The transformation of a new molecular entity into a marketed drug product takes many years, some say 12 years on average, and costs about $200 to $350 million. Twenty years ago, following the thalidomide tragedy, a fearful FDA stalled, and the time taken by the agency to review an NDA began, in some cases, to match the time required for the drug development process and to seriously erode patent life. The pharmaceutical industry pressed Congress for relief. With the passage of the Prescription Drug User Fee Act (PDUFA) by the US Congress in 1992, which permits the FDA to charge sponsors who submit NDA and BLA documents, with the stipulation that the additional revenue be used to hire more reviewers, the approval time (from submission of the NDA or BLA to approval date) has been reduced to about one-half. The FDA's current goal is to review 90% of submitted BLA and NDA applications within 12 months. The agency will strive to reduce this target to 10 months. Surveys suggest that the agency has been meeting its goals and is on track for meeting future goals. Some industry observers, however, fear that a spate of withdrawals of marketed prescription drugs for reasons of safety may make the FDA more cautious and increase approval time.
While the efficiency of the NDA and BLA review process has greatly improved, dramatically decreasing the time for regulatory review, the same cannot be said for overall drug development time, from identification of a new drug candidate to NDA or BLA submission, which has resisted the anticipated streamlining effects of new technologies and efficiencies.
■ 2.2. DIFFERENCES BETWEEN DEVELOPMENT OF BIOTECHNOLOGY PRODUCTS OF MACROMOLECULES AND CHEMICAL PRODUCTS
Unlike traditional drugs, which can be chemically synthesized and purified to homogeneity, biological macromolecules are often derived from living sources— human and animal tissues and cells and microorganisms. Therefore most biologic macromolecules are not easily characterized and refined to a high degree of purity. In the absence of well-developed standards for these products, CBER has developed guidelines to ensure that macromolecules approved for human use are manufactured under conditions that ensure batch-to-batch uniformity and that no infectious agents are inadvertently introduced into a product.
Before 1996 the FDA approved bio-pharmaceuticals through a dual process that required a Product License Applica tion (PLA) and an Establishment License Application (ELA) (Table 2.1). According to PHS rules, a "Responsible Head" had to be appointed to ensure the safety of the product manufactured by the sponsor. Because the FDA's philosophy was "the process is the product," the manufacturing facility was tightly regulated, requiring the pharmaceutical company to obtain an establishment license (through the ELA process) for manufacturing the biologic macromolecule before initiating any human clinical trials. In addition, up until 1996, any modification in manufacturing process and controls required preapproval by CBER prior to implementation.
In 1996, about 10 years after the introduction of the first recombinant DNA product for human use, the FDA modified and streamlined the approval process for biotechnology products considered to be "well characterized." These modifications, in essence, established the direction of how biologic macromolecules are researched and developed today in biotechnology-based and traditional pharmaceutical companies . "Well-characterized" biotechnology products include (1) synthetic peptides consisting of fewer than 20 amino acids, (2) monoclonal antibodies and derivatives, and (3) recombinant DNA-derived products. Anticipating future developments, the FDA is also prepared to consider DNA plasmid products as well-characterized when the first medicinal in this class is submitted for approval. CBER now approves well-characterized biophar-maceuticals under the BLA process .
The BLA strategy has significantly improved the process for approving bio-pharmaceuticals through reductions in paperwork and financial burden, a particular boon for start-up biotechnology-based drug companies. Drug sponsors are no longer required to manufacture the product in-house; contract manufacturers with established resources are now permitted to make the biopharmaceutical for both human testing and marketing.
■TABLE 2.1. Regulatory requirements for development of chemicals and macromolecules into drugs
Macromolecules Chemicals 1996 and Earlier Current"
Application NDA (New Drug and approval Application) process
BLA (Biologic License Application)
FDA center responsible for review
Quality control and assurance
Lot release requirement
Manufacturing process modification
Center for Drug Evaluation and Research (CDER)
No "Responsible Head" requirement
Any company can submit NDA without the requirement to manufacture the drug in house
Final product must be made under current good manufacturing process (cGMP)— emphasis placed on the final bulk product
Not controlled by CDER
No promotional material approval required after FDA approval for product marketing
Document manufacturing changes in annual reports
PLA (Product License Application) ELA (Establishment License Application)
Center for Biologics Evaluation and Research (CBER)
Designated "Responsible Head"
PLA can only be submitted by manufacturers of significant steps in process. More than one manufacturer can be licensed for a given product
"The product is the manufacturing process" —cGMPs from seed stock or first step onward evaluated with equal scrutiny
Every lot manufactured for marketing controlled by CBER
All promotional materials must be pre-approved
Approval required for every manufacturing change before implementation
No "Responsible Head" requirement'
The applicant may or may not own the manufacturing facilities. No requirement for contract facility to obtain a separate license
Regulated under analytical procedures and method validation, chemistry, manufacturing and control (CMC) documentation
No longer required, but must be made available upon request by CDER
Promotional materials are submitted to the FDA for information
Submit manufacturing changes and validation documents to FDA 30 days prior to product distribution'
"Elimination of ELA and PLA requirement, 14 May 1996 and replaced by BLA Federal Register, 63,147, 40858-40871 .
'15 October, 1996 , FDA final rule published through the President's reinventing government (REGO) initiative .
'Manufacture process modification, effective 7 October 1997 .
Other modifications to the regulatory requirements promulgated in 1996 and summarized in Table 2.1 are final rules on labeling, lot release, and manufacturing process modifications.With these changes in place, the development process of the well-characterized biopharmaceutical is approx imately in line with that of traditional drugs . In fact FDA has now committed to shift the regulatory responsibility of these recombinant products under CDER, and allowing its biologics division (CBER) to focus on vaccines, gene and cell therapies, and other blood products (Box 2.1.).
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