Phase 3: Clinical development

Time: 2-4 years

Cost: $10-500 million

Scale: kilograms of product (1,000 - 5,000 patients)

Success rate: 80%

During phase 3 trials, a company verifies the efficacy of its drug and monitors 1,000,000 patient volunteers for adverse events during long-term use. Less than a quarter of INDs make it all the way through phase 3 clinical trials, but the majority of products that begin phase 3 will make it through with their development programs intact.

The number of human subjects involved in a phase 3 study depends on the disease being studied. "Orphan drug status" granted by FDA means a therapeutic will ultimately treat a patient population of 200,000 or fewer, and such drugs receive special regulatory treatment because they will never be "blockbuster" sellers for the companies developing them. Without a large market awaiting the product, a company must have another kind of incentive to move forth with it, so regulatory agencies try to help lessen the cost of development for orphan drugs.

Phase 3 trials are expensive: Clinical monitoring of patients can include X-rays, blood tests, and other laboratory studies in addition to physician fees and required hospitalizations. Whereas classical pharmaceuticals go through two or more phase 3 trials, biopharmaceuticals usually require only one because a certain baseline efficacy is assumed based on the fact that living things make the chemicals themselves. A pre-BLA (biologics license application - described in the next chapter) meeting with FDA is optional at the end of phase 3.

Regulatory matters. While phase 3 studies are going on, preparations are made for submission of the BLA (for most biotech drugs) or the new drug application (NDA). BLAs are reviewed by FDA's Center for Biologics Evaluation and Research. NDAs are reviewed by the Center for Drug Evaluation and Research, which handles classical, small-molecule drugs and a small number of biotech drugs. Hormones (such as insulin and estrogen) are traditionally reviewed by CIDER, even through they are manufactured through biologic means. Biologics were traditionally more difficult to purify and characterize; modern biotechnology has resolved some of those challenges, but for now even well-characterized biologics are regulated separately from classical drugs.

In some cases, a biopharmaceutical company can get permission from FDA for expedited review. That fast track review allows a company to combine phase 2 and 3 clinical trials, shortening the approval process for new medicines that address serious and life-- threatening diseases. Such priority status gives FDA six months to review a BLA, whereas the time allowed for a standard application is 10 months.

Key Departments

The analytical laboratory is now performing continual methods validation and product characterization, testing for stability and consistency, and further refining the drug formulation. Chronic toxicology studies continue, and the animal laboratory is looking for reproductive side effects. That includes determining whether the drug product transfers across the placenta to a developing fetus and whether it may find its way into an animal's milk, in addition to looking at general effects on male and female fertility. Carcinogenicity studies in animals can take up to three years and may require several million dollars of investment, so they don't begin until a drug has reached the final stage and shown itself to be a good candidate for eventual approval.

The manufacturing department needs to have a good process under way by this point. The priority now is summed up as final formulation, fill-and-finish. If the product comes from the milk of transgenic mammals, it will have been scaled up to the species best able to produce the volume needed for the eventual market - goats, sheep, or cows, for example. Corn or tobacco plants may be used to produce the drug. Most biopharmaceuticals are produced by bacterial fermentation or eukaryotic cell culture (using cells from multicelled animals or yeasts). Such cell lines should be well characterized and optimized by this point. Production, validation, SOPs, and regulatory matters are increasingly crucial.

Whether in the sponsor company or at a CRO or CMO, the following departments and functions are involved in phase 3 trials: analytical laboratories, QA/QC, GMP compliance, regulatory affairs, manufacturing and production, and clinical development.

Equipment and Methods Used

Development staff understand that their project may die in phase 3 (although its chances have improved with each successful step through the development process). But they also know that if the company receives a license to market the drug, management will expect to have a full-scale manufacturing process ready to go as soon as possible. The biopharmaceutical company may have been surviving up to this point on venture capital and/or partnership money alone, and those investors will be looking for sales returns.

The manufacturing department continues to refine its production process, trying to find a balance between speed and efficiency in fill-and-finish. If liquid formulations go into vials or ampules too quickly, bubbles can form. Foaming is dangerous, causing delicate proteins to unfold or break. Because (as stated previously) proteins' actions depend on their three-dimensional structure, such denaturation destroys a protein's ability to perform its intended function in the body.

For the biopharmaceutical company's manufacturing and production department, the best choice might be to freeze-dry the liquid protein formulation into powdered (lyophilized) form. That in itself brings up a whole new set of problems. Those who administer the drug will have to reconstitute its formulation to prepare the injection.

Critical Concerns

Regulatory affairs personnel are now doing preparatory work on the BLA submission. The QA/QC department is ensuring that the experimental drug given to patient volunteers is truly the drug's pure and final form. If, during scale-up of the manufacturing process, significant changes were made between phase 1 and phase 3, the company may have to establish equivalency of formulations and processes. That, of course, means more testing and analysis.

If a product succeeds through phase 3 trials, it will need to go into full-scale production for the market (pending FDA's decision on the licensing application, of course). Often the manufacturing process is transferred from the smaller pilot plant to the large-scale facility in time for phase 3 trials, but if not, the transfer will begin during phase 3. Equipment for full-scale production must be formally qualified and instruments appropriately calibrated according to GMP requirements and industrial standards. Process validation must demonstrate comparability of the product manufactured to that made in the pilot-scale plant and that the process operates within the parameters and specifications that were set early on. Cleaning (and thus cleaning validation) has become a very important consideration, especially if the product will be made in a "multiuse" facility where other biologics are also made. Cross-contamination between processes must be prevented. Multiproduct facilities require more extensive validation efforts, but the cost is usually offset by using the equipment, suites, and utilities more efficiently than if the facility were devoted merely to a single manufacturing process.

Often during process transfer, validation studies are performed by process scientists with production personnel alongside to learn; production staff in training do qualification work, observed and assisted by development personnel. By now the studies should not be as complex as those run earlier, serving mainly to confirm operational parameters and verify the success of transfer. Not only is each section of the process tested, but the final system as a whole will require test runs as well.

Guidance

GMPs are required by law in any biotech plant making drug products for human use, even in early clinical trials. By phase 3, GMP compliance should be at its most rigorous. A regulatory affairs executive has described several significant differences between pre-- GMP and fully GMP-compliant companies. One such difference is that, in a GMP company, the number of people involved in production, testing, support, and administration at least equals - and may be twice as great as - the number of research scientists, who far outnumber them in a young company still primarily involved in early development.

Manufacturing and support personnel are not allowed to develop off-the-cuff solutions to problems that arise. They must follow accepted, validated, approved methods and standard operating procedures. Changes and modifications must be approved through official means. GMP regulations require documenting all work done, all deviations and investigations into them, all decisions and review (sometimes with formal validation protocols), all data collection and analysis, and all reporting. Communication is much more formal in a GMP-compliant company than in a research organization. That is the only way for the company to be able to back up its claims during subsequent reviews or FDA inspections.

On the Horizon

As a biopharmaceutical company looks forward to putting its product on the market, it must consider the eventual scale of production. If that scale is large enough, transgenic technology may provide the best answer. Several drugs now in clinical trials are produced in the milk of transgenic rabbits, sheep, goats, or cattle. And there are other amazing transgenic proposals - all still experimental, at this point. A couple of companies will offer therapeutic proteins from the eggs of transgenic hens. Potatoes are producing vaccines for E. coli and cholera, Tobacco plants are making human hemoglobin in their seeds and roots. Transgenic corn is producing therapeutic proteins. And a California company is working toward other plants that make human antibodies. Development of transgenic plants may advance the concept of plant cell culture as a production means, as well.

Transgenics presents a number of challenges to drug developers. It is true that the technology can offer much higher yields than more traditional biotech methods. But questions remain about how to purify a pharmaceutical protein from a mixture containing many other proteins and fatty acids like those present in milk. Purification from plant tissue may be less problematic. Humans have far fewer pathogens in common with plants than with mammals. But the herbicides and soil components that are familiar to farmers might present a problem for injectable drugs, which must be very pure to be safe.

The 1997 announcement of Dolly the cloned sheep brought the idea of cloning into the public spotlight. The nuclear transfer research that led to her creation aims to produce transgenic animals faster for protein production. But the technology raises ethical questions. Now the concept of transgenic species - particularly genetically modified food and plants - is the subject of heated debate all over the world. Those and related issues need to be resolved before transgenics can become a mainstream technology.

[Sidebar]

21 CFR Part 11: Drug Development in a Digital Age

[Sidebar]

Since 20 August 1997, FDA has considered electronic records to be equivalent to paper records and electronic signatures to be equivalent to traditional handwritten signatures if certain criteria are met. That means that INDs, BIAs, and NDAs, among others can be submitted electronically. However, validation is required for computer systems that are used to create, modify, maintain, archive, retrieve, or transmit data intended for submission.

[Sidebar]

You might think that electronic filing would be easy; after all, computers have been a staple of the business and scientific world for more than two decades now. But security and compatibility between networks and operating systems have not been simple to achieve. Electronic filing of large, sensitive documents like drug marketing applications requires dependable electronic signatures and cross-platform file formats. Old computers and digital lab equipment, called legacy systems, must be maintained if records were created on them, and those records must be retained securely so that regulators can instantly reconstruct analyses. Regulators want to be able to trace final results back to the raw data using the same tools the user had when the data were generated.

[Sidebar]

Security is a big concern in computer system validation and must ensure authorized access only, unique user IDs and passwords, forced log-offs for long inactive periods, local date/time stamps, and user-independent, computer-generated, timestamped audit trails. Data integrity and confidentiality is required for all computerized laboratory and production equipment.

[Sidebar]

The Part 11 rule applies to good laboratory practices (GLPs), good clinical practices (GCPs), and current good manufacturing practices (CGMPs), collectively referred to as GxPs. It applies to everything regulated by FDA, including medical device manufacturers, blood banks, foreign companies, and pharmaceutical and biotech production. The first warning letters and FDA 483s for electronic record/electronic signature violations were issued in November 1997 and are still being issued, but Part 11 is now appreciated, accepted, and supported by most of the industry.