The Road to Drug Approval
The U.S. Food and Drug Administration (FDA) drug approval process has nine stages (fda.gov). They are organic research; target identification and validation; determination of a lead compound; ADME/tox testing; compound optimization; preclinical testing; investigational new drug (IND) application; clinical trials (Phases 1, 2, and 3); new drug application (NDA); manufacture and scaling; and Phase 4 testing. Each step is described in detail in this appendix, with an eye to how it contributes to the ultimate expense of drug development (see fda.gov).
Organic Research
The initial step is a characterization of the disease or disorder that is in need of a new therapeutic approach. Academic medical centers (AMCs) such as Cleveland Clinic might seem to have an advantage in problem identification because of the volume and variety of the pathologies, but the understanding of disease processes isn’t limited to AMCs. Research universities, government laboratories, and industry-based scientists all are toiling to produce meaningful discovery science.
The understanding of basic chemistry, genetics, protein synthesis, and even potential chemical interactions informs initial paths. In addition to knowledge, there is also the need for insight; it takes a level of sagacity to understand a disease process and its relationship to a new drug treatment.
Target Identification and Validation
Understanding a disease needing treatment with a new drug therapy and selection of a molecular target is like looking at something with the naked eye versus an electron microscope. The target must be as focal as a single molecule, protein, or gene.
The target must also be “drugable,” meaning a new compound can influence its operation, block its synthesis, or alter its expression. Early studies that establish some form of cause and effect are crucial. If a specific molecule can be implicated in a disease and shown to be influenced or modified by a drug family, then it may be worthwhile to allocate resources to the process of drug discovery.
Determination of a Lead Compound
The processes thus far can be characterized as basic research and development. But once the search for a specific molecule commences, innovators are pursuing drug discovery. Whether it’s through observation of natural phenomena, creation at the bench or computer of molecules with certain structural characteristics, or high throughput screening, filters are necessary to identify the lead compound.
Lead compound designation is not equivalent to calling a newly identified molecule, whether discovered or synthesized, a new medicine. An extraordinary volume of lengthy, expensive testing awaits.
ADME/Tox Testing
Pharmacokinetics refers to how the body handles exogenous substances. The evaluation of lead compounds consists of a battery of tests to determine how the body will respond to and tolerate the substance. The acronym ADME/tox represents what innovators and scientists consider when sifting through lead compounds: absorption, distribution, metabolism, excretion, and toxicity.
Compound Optimization
Lead compound selection is both a winnowing and a tweaking process. Sophisticated medicinal chemists can alter subtly the structure of molecules to behave differently regarding any of the ADME/tox criteria.
Fortunately, much of this work can now be performed on high-powered computers through finite element analysis rather than arduous and repetitive bench testing, but the concept is the same, and trial and error still plays an important role. Dozens or even hundreds of analogs can be tested to determine the influence a small chemical alteration has on the molecule’s performance. Because this is typically the step before preclinical trials, many experienced drug developers consider some of the practical ramifications of altering the chemistry. These include, but are not limited to, how the drug may be produced, its interactions with the inert components or vehicles that may hold it together, its best delivery form (taken by mouth, injected, inhaled, etc.), and even large-scale manufacturing.
Preclinical Testing
We are all aware of the lengths that the FDA goes to to protect our citizens. Preclinical testing provides the FDA with one of its primary tools to ensure safety and collect data vital to move the new drug successfully through the approval process.
Voluminous testing at the laboratory bench in cell culture or in animal models is conducted to determine a handful of candidates that later will be studied in clinical trials. Although many factors are considered, efficacy and safety rank at the top, and the data must be compelling and reproducible.
IND Application
The filing of an investigational new drug application (IND) with the FDA is an important milestone marking the intersection of investigational chemical development with the regulatory apparatus. The IND includes the accrued data from the previous bench work and preclinical trials. Moreover, the IND must describe an expanded plan for a clinical trial.
The FDA isn’t the only governing body policing the progress across the threshold between preclinical and clinical testing. The institutions at which trials will be performed have a powerful mechanism to ensure safety of the study participants, the institutional review board (IRB).
Essentially every AMC and research university has an IRB. This body is composed of researchers, clinicians, statisticians, and administrators who understand the processes of large-scale investigation involving human subjects. IRBs have experience in study design and the specific focus of developing the appropriate informed consent required from potential study participants.
From this point, regular, detailed information exchange will take place between the sponsoring organization and the FDA. If safety concerns arise, either the institution or the FDA can halt the trial. Trials of investigational drugs also have been truncated because the nascent therapy is so effective that it would be considered unethical to subject it to an even more lengthy regulatory process. Regardless of eventual outcome, the IND is one of the most critical stages in drug development.
Clinical Trials
The compounds have passed through multiple steps designed to weed out characteristics that could be considered harmful or render the molecule(s) ineffective. The ultimate laboratory is the human subject.
Not only are students of innovation familiar with the phases of clinical trials, even popular media often report promising new drugs transitioning from one phase to another. The phases of clinical trials have become almost common vernacular, as anxious and engaged observers who suffer from specific diseases closely follow the progress of promising compounds.
The three main phases demonstrate a logical progression, from testing in healthy volunteers to larger groups of patients afflicted with the target disease or disorder. In Phase 1, usually 50 to 100 healthy subjects receive the candidate drug. Roughly the same pharmacokinetic battery of testing described earlier (ADME/tox) is conducted. The response of the subjects (not considered patients) is monitored through clinical and laboratory examinations. Parameters like dosage ranges may be manipulated during this phase, while the drug is evaluated for safety and effectiveness.
In Phase 2 clinical trials, the candidate drug touches patients for the first time. Proven safe and effective in healthy volunteers, a set of patients with the disease or disorder receive the drug and are monitored for side effects ranging from allergies to drug interactions. The developers and principal investigators evaluate the clinical response to the drug: is it affecting the disease state in a predictable way?
Statisticians and clinicians work side by side during all phases, but especially in the transition between phases 2 and 3, to determine how many patients must receive the candidate drug to ensure statistical significance. The typical size of the study population in Phase 2 may be 100 to 500, but in Phase 3, the number is perhaps 10 times larger.
Phase 3 trials are both the lengthiest and most expensive. While a Phase 2 trial conceivably could be conducted at a single hospital or integrated healthcare system, Phase 3 requires a multicenter trial network carefully coordinated by the principal investigator.
Conducting large-scale clinical trials is a commercial activity of its own; in fact, it’s big business. An estimated nearly 40,000 new drugs or devices are being tested in clinical trials at any given time. Rarely would this specific endeavor reside within an innovation and commercialization function like Cleveland Clinic Innovations. Clinical trials typically are orchestrated by industry experts who call upon veterans at leading AMCs or in private medical offices who engage frequently in such studies.
NDA
If all systems are go after the three sequential clinical trial phases, it’s time to prepare the voluminous new drug application (NDA) for submission to the FDA. In addition to all of the data aggregated in the steps just outlined, descriptions of how the drug will be manufactured at scale and labeled for physician prescribers and the public is included in the NDA.
There is no single formula that leads to FDA approval or denial of a new drug. As the agency sifts through tens of thousands of pages of data detailing years of work and scrutiny of the new compound, the FDA is essentially weighing a risk/benefit ratio. No drug presents zero risk. It is the purview of the FDA to determine whether the associated risks outweigh the inherent benefits.
The FDA maintains extraordinary expertise in determining drug safety and efficacy. The FDA also enlists advisory committees composed of experts in particular fields, unassociated with the commercial development of the specific drug. Although the FDA often follows the recommendations of the advisory committees, it is not required to do so.
The drug can be approved, denied, or deemed approvable, which requires the sponsor to provide additional information.
Manufacture and Scaling
It is no mean task to move from research-scale compound preparation to commercial grade drug production. Even a slight variation in the composition of a drug is unacceptable for obvious reasons. Essentially every drug is distinct in its method of manufacture, so new or repurposed facilities are required. The FDA also has guidelines for good manufacturing practices (GMP) that must be met to engage in industrial-scale production of drugs. Constant testing for quality is conducted by both the commercial concerns and independent agencies. Action plans to stop production and even recall medicines must be in place.
Phase 4 Testing
Phase 4 clinical trials are conducted on patients who have been taking a specific new drug to detect its long-term effects. These trials are conducted over extremely lengthy periods involving the monitoring of massive numbers of patients.
This episodic or continuous monitoring checks long-term safety and efficacy profiles and determines unique, subtle effects. The testing requires what statisticians call power, which allows calculation of the minimum sample size required to demonstrate an effect of a given magnitude. As power increases, the chance for false negative results decreases.
Drug discovery is arduous and expensive. For the patients in need, and those engaged in the odyssey to bring new compounds to market, the transit from the medicinal chemistry performed at the laboratory bench to the shelf of the pharmacy or hospital formulary can’t be fast enough. However, public safety is the paramount concern. Among all the domains of contemporary innovation, the development of “molecules” (diagnostics and therapeutics) may require the most time, money and level of collaboration between the public, academic and private sectors.