A drug is not born as such. It does not spring from the forehead of Zeus—safe, effective, and ready to use. A drug begins instead as a pyridine, a nucleic acid, a peptide, an antibody, or some other thing of unknown safety and unknown therapeutic value. For a princely sum, with luck, and with years of methodical effort, this untested thing can become a means to save lives and reap a fortune for its maker.
The United States has one of the world’s most rigorous systems for ensuring that drugs are safe and effective. It is therefore not uncommon for a drug’s approval in this country to occur more than a decade after discovery and testing begin. Given the rigor of its approval system, the United States is also one of the world’s most expensive places to develop a drug. Although estimates of the cost of bringing a single drug to market vary, it typically exceeds $1 billion. This amount also includes failed drug development attempts and the overall costs of running research and development programs.
The fruits of this discovery, development, and testing are commonly known as innovator drugs. This chapter is devoted to innovator drugs, both small-molecule and biologic. It introduces key steps and hurdles on the long and costly road to obtaining FDA approval for these drugs.
The approval pathways for innovator biologic drugs and small-molecule drugs are remarkably similar despite the chemical differences between these types of drug. It is for this reason that we address both innovator drug types in a single chapter.
Generic drugs and their biologic counterparts, biosimilars, have a common mission of lowering drug costs. For a host of reasons, though, the laws governing these two non-innovator drug types differ in important ways. We therefore cover these non-innovator drug types separately. Chapter 15 discusses generic drugs. It also introduces the laws governing generic drug approval, and the legal relationship between a generic drug and its counterpart innovator drug. Chapter 16 discusses biosimilars and explores the unique challenges inherent in approving such chemically complex non-innovator drugs.
Let us begin this discussion by defining a small-molecule drug as one having a molecular weight below one thousand Daltons. This size range notably excludes monoclonal antibodies and other large biomolecules that fall, instead, under the rubric of biologic drugs. Yet, it includes a vast array of drugs such as alkaloids, steroids, pyridines, and countless others. Indeed, before the advent of biotechnology and the biologic drugs it ushered in, the terms drug and small-molecule drug were practically synonymous, as virtually every drug of that era was a small molecule.
Every drug must either be found or created. At the research stage, scientists identify—that is, find or create—compounds that are candidates for treating a particular disease or class of diseases. These methods often involve screening compound libraries and performing combinatorial chemistry.
Once they identify a candidate compound, researchers test its behavior in vitro and in vivo. At this preclinical development stage, researchers establish therapeutic proof of concept using animal models for the target disorder. They also use animal tests to gauge the drug’s likely toxicity in humans. Importantly, using nothing more than animal and in vitro tests, researchers must determine the most appropriate dosing regimens, formulations, and delivery routes for starting human clinical trials. Researchers must determine, for example, how much of the candidate compound (e.g., in mg/kg or g/subject) should be administered to subjects in the first human trial. Researchers must also determine in what form (e.g., which salt and/or polymorph), in what formulation (e.g., tablet, injectable aqueous solution, or topical lotion), and by what route (e.g., orally, intravenously, or transdermally) the compound should be delivered.
EXAMPLE 14.1
Company X makes and sells topical products for treating skin disorders, including psoriasis. The company wishes to develop a new topical psoriasis drug.
Toward that end, scientists in Company X’s psoriasis product division acquire a library of fifty thousand synthetic compounds in hopes that some will have anti-psoriatic activity. The compounds are retinol derivatives made using combinatorial chemistry.
The scientists use an in vitro high-throughput assay to test each compound for its ability to nonlethally inhibit skin cell growth. Of the fifty thousand compounds tested, two hundred show the desired level of nonlethal inhibitory activity. The scientists then test each of these two hundred compounds in vitro using more accurate, yet cumbersome, skin cell–based assays. By doing so, the scientists identify twenty compounds, namely, X1–X20, having desirable inhibitory activity.
The scientists test the in vivo activity of X1–X20 using a mouse model for psoriasis. In this way, they identify ten candidate compounds having enough anti-psoriatic activity to warrant further testing. Those compounds—X1 through X5 and X11 through X15—are further tested in mice and larger animals for toxicity and ideal dosing. The scientists also prepare various topical formulations of X1 through X5 and X11 through X15 and test them ex vivo on human skin to identify the most effective formulation.
Based on these preclinical experiments, Company X’s scientists identify X3 as the candidate compound for clinical testing. Toward that end, and based on animal safety and efficacy data, the scientists also identify a topical cream formulation having a defined X3 concentration, as well as a once-daily dosing regimen, that they can propose for use when clinically testing X3.
It is self-evident that testing an investigational new drug on a human be based on a reasonable belief that doing so will be safe. If the investigational new drug, or drug candidate, has never been tested on humans, this belief must be based solely on preclinical data. Where human data already exist (e.g., from a clinical trial directed to a different indication), those existing human data, together with new preclinical data, can more thoroughly support the belief that clinically testing this drug candidate for its new indication will be safe.
Regardless of the data available, the investigational new drug application (IND) is the FDA’s procedural means for starting a drug candidate’s clinical testing. The nature and amount of information that an IND sponsor must submit varies depending on the drug candidate, the contemplated trial design and duration, and other factors. However, there are at least three types of information at the heart of an IND.
The first is information from pharmacology and toxicology studies in one or more suitable animal models of the disease to be treated. The study results must show effectiveness in at least one animal model. They must also support the belief that the drug candidate is reasonably safe for testing in humans. Of course, human data are also included—and ideal—if available.
The second is information satisfying the FDA’s Chemistry, Manufacturing, and Control requirements. This information relates to the “drug substance” (i.e., the active ingredient) and “drug product” (i.e., the finished dosage form). It includes, among other things, information relating to methods of manufacture, stability, and impurities. This and related information aid the FDA in assessing the drug product’s suitability for human testing.
The third is information about the proposed clinical trial protocol. This includes, for example, the number, ages, genders, and health status of the proposed test subjects; the proposed dosing, formulation, and administration route of the drug candidate; and the identities and credentials of those who will conduct the clinical trial.
An IND goes into effect quickly. There is no need for a protracted negotiation or a Byzantine paper chase. Barring an adverse measure by the FDA such as a clinical hold, an IND goes into effect thirty days after the FDA receives it. After that, the proposed trial may begin.
Meanwhile, the IND remains a living document throughout the clinical trial process. That is, the sponsor may amend the IND and submit required reports and other documents as clinical testing progresses.
Showing that a drug candidate works safely in an animal model is a key step on the road to FDA approval. But, it is merely one of many key steps. The drug candidate must, of course, also work safely in humans. That is, it must be safe and effective for its intended purpose.
For every drug candidate that is safe and effective in humans, there are many more that are not. Indeed, at the start of a drug candidate’s clinical testing, chances are that it will fail in one way or another. What is more, in the likely event that a drug candidate fails in the clinic, it might not do so until its sponsor has already expended years of effort and spent millions of dollars toward that end. So, it is not hyperbole to say that clinical testing is the ultimate hurdle on the road to FDA approval.
With certain exceptions discussed later in the chapter, clinical trials proceed in three parts, namely, phases 1–3. Each phase has a distinct purpose, and phases 1–3 progress in terms of cost, complexity, and time. Phase 1 is the least expensive, shortest, and simplest, and phase 3 is the costliest, longest, and most complex.
The FDA’s Center for Biologics Evaluation and Research (CBER) has jurisdiction over approving blood products, cellular therapies, vaccines, and gene-based products. The FDA’s Center for Drug Evaluation and Research (CDER) oversees clinical trials for drug candidates—particularly small-molecule drug candidates—outside CBER’s domain. In that capacity, CDER officials frequently and substantively interact with sponsors and investigators throughout this long and uncertain process.
Above all else, a drug must be safe. It follows that since a drug must be given at a specified dose, the drug must be safe at that dose.
In a phase 1 trial—typically the first test of a drug candidate in humans—investigators determine whether the drug candidate is safe and determine the maximum dose at which it remains so. In this regard, they also begin to identify the drug candidate’s adverse effects. Furthermore, phase 1 trial investigators normally measure the drug’s pharmacokinetics, pharmacodynamics, and, whenever possible, early evidence of efficacy. This phase usually takes less than one year to complete. It also typically uses fewer than one hundred subjects who, depending on the drug candidate being tested, are either patients or healthy volunteers.
EXAMPLE 14.2
Company X makes and sells small-molecule anticancer drugs.
Scientists at Company X develop CX1, a new derivative of paclitaxel (Taxol). They also perform in vitro and animal studies on CX1. The resulting data show this compound’s promise as a first-line treatment for breast cancer in humans. Company X wishes to clinically test CX1 for this indication so that, ideally, it can market CX1 in the United States.
Toward that end, Company X submits an IND to the FDA for CX1, a compound that has never been used in humans.
In the IND, Company X provides detailed information about (i) CX1’s cancer cell–specific toxicity in relevant human cell culture experiments, and (ii) CX1’s pharmacodynamic and pharmacokinetic properties in animal models of human breast cancer (e.g., transgenic mouse models). Company X also provides CX1’s chemical structure and physical properties, as well as methods for making CX1 in amounts and at purity levels suitable for clinical trials.
In Company X’s proposed clinical trial, the IND includes a proposed phase 1 study to demonstrate, among other things, CX1’s safety in humans. Here, Company X specifies that the study will include fifty patients with breast cancer within defined age ranges and having defined breast cancer types, defined disease stages, and defined treatment histories. The IND describes the proposed concentrated CX1 formulation, pre-administration dilution procedure, intravenous administration route, and regimen for dose escalation and other safety studies. For phase 1, this regimen requires intravenously administering single and biweekly CX1 doses ranging from 50 mg/m2 to 150 mg/m2 per subject, as appropriate.
The IND includes many other parts, such as information about the investigators and descriptions of observations and measurements that the investigators will make during the trial (e.g., pharmacodynamic and pharmacokinetic data and adverse reactions).
Company X will be free to begin its proposed CX1 clinical trial thirty days after the FDA receives its IND, barring contrary instructions from the FDA. Company X will also be free to amend the IND in accordance with the clinical trial’s progress and will be obligated to submit certain reports and other required supporting information as the clinical trial moves forward.
EXAMPLE 14.3
Thirty days after submitting its IND, Company X begins its phase 1 trial of CX1. In that regard, the investigators test CX1 as proposed. That is, they administer it to fifty patients with breast cancer within defined age ranges and having defined breast cancer types, defined disease stages, and defined treatment histories. They do so intravenously using the proposed injectable CX1 formulation at single and biweekly doses ranging from 50 mg/m2 to 150 mg/m2 per subject, as appropriate.
The phase 1 trial data show that like paclitaxel, CX1 is well tolerated at the doses tested, and the maximum tolerated dose was not reached. These data also show that CX1’s pharmacokinetic profile is similar to that of paclitaxel.
In addition to establishing the pharmacokinetics and relative safety of CX1, the phase 1 study also yields preliminary data consistent with CX1’s ability to treat breast cancer. (Note: As explained later in the chapter, demonstrating CX1’s efficacy will require successfully completing phase 2 and 3 trials.)
Even a safe drug is not a drug unless it works. Enter the phase 2 trial.
A phase 2 trial normally lasts from several months to two years. Depending on the indication, it can involve up to several hundred patients. The trial is meant to show, at least preliminarily, that a drug candidate works in the manner intended. This phase also builds on what was learned during phase 1 about safety and side effects.
Based on phase 2 safety and efficacy data, an investigator can finalize the treatment protocol to be used in the phase 3 trial. In that regard, and to maximize the chances of success for the phase 3 trial, its design should mimic that of the successful phase 2 trial.
EXAMPLE 14.4
Based on the successful completion of its phase 1 study, Company X amends its IND to more accurately set forth the protocol for its phase 2 study. Company X then begins that study as proposed.
In total, the study involves three hundred patients. The investigators intravenously administer CX1 at an initial dose of 100 mg/m2 every two weeks for three cycles (Regimen 1).
The Phase 2 data show that like paclitaxel, CX1 causes anaphylaxis and severe hypersensitivity reactions. However, CX1 has this side effect in only 1–3 percent of patients, as opposed to the 2–4 percent of patients afflicted with these side effects after receiving paclitaxel. The trial data do not show any other adverse effects that are more severe than those resulting from paclitaxel treatment.
Based on CX1’s phase 2 data, Company X again amends its IND to fine-tune its phase 3 study protocol.
Ideally, the phase 2 data will suggest that a drug candidate is safe and effective for its intended purpose. However, phase 2 data, by themselves, are not sufficient for marketing approval, however favorable they may be. A trial sponsor must instead provide far more clinical data to establish safety and efficacy. Such is the phase 3 trial’s role.
Phase 3 studies can involve hundreds or even thousands of subjects. It is not uncommon, though, for these studies to be much smaller under certain conditions. The size of a trial depends on various factors, such as drug indication. They are typically international multicenter trials. These studies produce the bulk of efficacy and safety data needed to understand the benefits and risks of a drug candidate prior to approval. As mentioned, phase 3 studies are the most time consuming and the most expensive to conduct.
EXAMPLE 14.5
Based on the successful completion of its phase 2 study, Company X again amends its IND to finalize its proposed protocols for the phase 3 trial.
Company X then begins the proposed studies, which are multicenter and involve two thousand patients in several countries. In relevant part, based on the phase 2 data, the investigators intravenously administer CX1 at a reduced dose of 80 mg/m2 every two weeks for three cycles (Regimen 2).
The phase 3 trial data show that Regimen 2 causes anaphylaxis and severe hypersensitivity reactions in only 0.5–2 percent of patients. This is far lower than the 1–3 percent incidence seen with Regimen 1. Meanwhile, Regimens 1 and 2 have comparable efficacies. The phase 3 data do not show any adverse effects more severe with Regimen 2 than those resulting from Regimen 1. Because of the size of the phase 3 study, these results are statistically significant.
Additionally, the phase 3 investigators determine that CX1 may be administered to a patient afflicted with a solid tumor if her baseline neutrophil count is at least 1,200 cells/mm3. By contrast, paclitaxel cannot be administered to patients with solid tumors having baseline neutrophil counts below 1,500 cells/mm3. Thus, the phase 3 data reveal yet another advantage of CX1 over paclitaxel.
A phase 3 trial, or a phase 1 or 2 trial for that matter, can yield valuable information about a drug candidate beyond whether it is safe and effective. Importantly, a clinical trial can yield inventions relating to the drug candidate.
EXAMPLE 14.6
Again, administering CX1 according to Regimen 2 (i.e., 80 mg/m2) is safer than doing so according to Regimen 1 (i.e., 100 mg/m2), and both regimens have comparable efficacies.
While testing Regimen 2, the investigators discover that at this reduced dose, it is unnecessary to premedicate patients before administering CX1 to prevent anaphylaxis and severe hypersensitivity reactions. This finding is unexpected in view of paclitaxel’s dosing and administration instructions. Specifically, to prevent anaphylaxis and severe hypersensitivity reactions, paclitaxel administration requires premedication with agents such as dexamethasone, diphenhydramine, cimetidine, and ranitidine.
Company X believes that this discovery is the basis for a patentable method, namely, using CX1 to treat a non-premedicated patient with breast cancer. Company X sees this invention as valuable, in that it overcomes one of paclitaxel’s shortcomings.
Company X therefore files a U.S. provisional patent application claiming a treatment method comprising intravenously administering CX1 to a patient with breast cancer according to Regimen 2, wherein the patient has not already been treated with dexamethasone, diphenhydramine, cimetidine, ranitidine, or the like.
In some cases, it is inexpedient to conduct clinical trials by completing phase 1 before phase 2 and then completing phase 2 before phase 3. The FDA therefore permits sponsors to combine whole and partial trial phases as appropriate given the facts. For example, a sponsor may opt to perform a phase 1/2a trial on patients rather than complete a phase 1 trial on healthy volunteers prior to beginning a phase 2 trial on patients. Similarly, a sponsor may choose to perform a phase 2/3 trial rather than separately and sequentially performing phase 2 and 3 trials. Once again, the FDA permits using these alternative clinical trial phases so long as the relevant data and other facts support doing so.
As a separate matter, there are often situations in which the public’s need for a drug to treat a life-threatening or other serious condition outweighs its need for the drug to undergo the time-consuming and costly approval route that the FDA normally requires. To address such situations, the FDA has established four special and overlapping ways to speed approval. Although they all hasten drug approval, these approaches have distinct selection criteria and address different stages of the development and approval processes.
The Fast Track approach speeds the FDA review process during the development of a drug that treats a serious condition (e.g., AIDS, Alzheimer’s disease, or cancer) and fills an unmet medical need by potentially being the first drug, or a better drug, for treating that condition. Fast Track status is requested prior to a new drug application (NDA) or biologics license application (BLA) submission, and as early as an IND submission.
The Breakthrough Therapy approach speeds the FDA review process during the development of a drug that shows early clinical evidence of substantial improvement over available therapies.
Accelerated Approval permits using surrogate endpoints to approve a drug that treats a serious condition and fills an unmet medical need. This approach is relevant to a drug candidate targeting a serious condition such as a tumor, in that less time is needed to measure a surrogate endpoint like tumor shrinkage than to measure a more meaningful clinical endpoint like increased survival. Accelerated Approval is conditioned, though, on subsequently completing a phase 4 study using the corresponding clinically meaningful endpoints.
Finally, a Priority Review designation targets an approval application (i.e., an NDA or BLA) and reduces the time period for the FDA to act on the application from ten months to six months.
For every drug candidate, there is a story of how it overcame steep odds to reach the point at which marketing approval is a likely outcome. Before the FDA can approve an innovator drug candidate, its sponsor must tell this story to the FDA. In the United States, the New Drug Application (NDA) is the vehicle for doing so. In essence, an NDA must demonstrate that a drug candidate is safe and effective for its intended purpose and that its benefits outweigh its risks.
Not surprisingly, an NDA is usually an immense and comprehensive submission having myriad parts. An NDA describes the proposed manufacturing method and controls to ensure that the drug, once approved, maintains its identity, strength, quality, and purity. It presents all preclinical data on the drug’s pharmacology and toxicology, whether obtained in vitro or in vivo. Naturally, it presents all clinical data and their relevance to the drug’s pharmacokinetics, bioavailability, efficacy, and adverse effects. An NDA must also include information about patents covering the drug and its uses (a topic addressed in chapter 15). Importantly, it must propose labeling information that precisely describes the drug, its dosage and administration, its benefits and risks, and the basis for approving the drug. The list goes on.
As one would expect, the FDA reviews each complete NDA with the substantive rigor and depth it deserves. This process includes analysis by a team of FDA experts on medicine, pharmacology, toxicology, chemistry, statistics, and other relevant fields. It may also require FDA advisory committee input.
The NDA process is also an interactive one between the FDA and the drug sponsor, as are the pre-NDA stages. The FDA will not approve a drug candidate unless and until it believes that the drug is safe and effective, its benefits outweigh its risks, its manufacturing methods and controls are sufficient, and its proposed labeling is appropriate. The sponsor’s positive interaction with the FDA, and prompt corrective action when necessary, help the FDA reach this point.
Once the FDA approves an NDA, the sponsor is free to market the approved drug in the United States for use in treating its approved indications as described in its approved label.
NDA approval marks the end of a drug’s long, expensive, and uncertain journey from drug candidate to marketable product. It does not, however, end the FDA’s interest and involvement in ensuring the drug’s safety and efficacy. At most, the clinical data supporting an NDA form a limited picture of a drug’s safety and efficacy. Those data arise from testing a drug candidate on a finite number of subjects for a finite time. Given these limitations, phase 1–3 trials may fail to identify rare but serious side effects, large differences in efficacy between patient subpopulations, and other hidden dangers. Although this shortcoming might not prevent the FDA from approving a drug in the first place, it does fuel an interest by the FDA and sponsor alike in better understanding, in a real-world context, how the drug works, what dangers it poses, and to whom it may pose danger. The fact that the approved drug is now marketed only strengthens this interest.
The post-marketing study, or phase 4 trial, helps to accomplish this goal. It is used often and permits a sponsor to test its approved drug on thousands of patients over the course of years. Phase 4 data can guide the drug’s sponsor in fine-tuning the label to reflect the safest and most effective way to administer the drug and to more accurately warn of the drug’s side effects and patient subpopulations most at risk.
In addition to its involvement with phase 4 trials, the FDA independently and proactively monitors the safety, manufacture, and advertising of drugs it has approved. Depending on its findings, the FDA can compel a sponsor to amend its drug label or, in extreme cases, recall the drug. Of course, a sponsor can also proactively recall an unsafe drug from the market.
Often, a drug approved for one indication is found to have another indication. This new indication might be just as important—and profitable—as the original indication. What is more, clinically testing an approved drug for a new indication can be faster and less costly than testing a new drug. For these reasons, drug companies devote considerable resources to searching for and developing new indications for approved drugs.
The §505(b)(2) pathway is the primary route for getting the FDA to approve a new indication for an approved drug. This pathway is named after the relevant section of the FDCA. In contrast, the §505(b)(1) pathway—the traditional NDA—is the route for getting the FDA to approve a drug product the active ingredient of which has not yet approved. This is the pathway we have already discussed. We further describe the §505(b)(2) pathway in chapter 15.
Biologic drugs are the new kids on the pharmaceutical block. Yet, these drugs—known as biologics—are here to stay and already play a vital role in treating life-threatening and other serious diseases. Their commercial success reflects their therapeutic success. Indeed, erythropoietin drugs such as Amgen’s Epogen, Johnson & Johnson’s Procrit, and Roche’s Eprex, and antibody drugs such as AbbVie’s Humira and Roche’s Rituxan, are among the best-selling drugs on record.
The FDA defines biologics broadly. They include cells, viruses, antitoxins, vaccines, blood components, and more. However, monoclonal antibodies and other large-protein drugs form the lion’s share of the biologics market.
Biologics and small-molecule drugs differ profoundly. The most striking disparity is size. A monoclonal antibody drug, for example, is larger than a typical small-molecule drug by orders of magnitude. Because of their size and attendant three-dimensional complexity, biologics can also bind, block, stimulate, irradiate, and otherwise affect their targets with a specificity and potency that many small-molecule drugs lack.
To manufacture a biologic, one must use methods far different from those for making a small-molecule drug. Making a small-molecule drug requires little more than the proverbial test tube. Yet, only a living cell can produce a biologic. This need for in vivo production, along with biologics’ size and complexity, conspire to unleash a world of variables that can fundamentally alter the resulting drug. For example, a monoclonal antibody drug produced under nonideal conditions can be defective by virtue of improper protein folding, incomplete crosslinking, aberrant acetylation, or faulty glycosylation. Not only might the defective antibody lose its therapeutic effect, it might also trigger anaphylaxis or other adverse reactions in patients.
Despite the differences between biologics and small-molecule drugs per se, their development and approval pathways are largely the same. A biologic arises from discovery and experimentation, as does a small-molecule drug. A biologic candidate is tested preclinically, as is a small-molecule drug candidate. Subject to an IND, a biologic candidate is usually tested in three clinical phases, as is a small-molecule drug.
Like a small-molecule drug, a biologic is the subject of an application for marketing approval, which in this case is a Biologics License Application (BLA) rather than an NDA. An NDA and a BLA each tells a drug candidate’s story. Also, like an NDA, a BLA provides information on the drug candidate’s chemistry, structure, preclinical and clinical data, pharmacokinetics, bioavailability, toxicology, efficacy, and labeling. Moreover, a BLA and an NDA must both describe proposed manufacturing methods and controls to ensure drug quality, although a BLA must do so in a way that addresses the dangers unique to making biologics.
For the most commercially important biologics, such as therapeutic monoclonal antibodies, the FDA’s CDER oversees the testing and approval of drug candidates, just as it does for small-molecule drug candidates. As noted, CBER oversees the approval of certain other biologics, such as cellular therapies, vaccines, and blood products.
Regardless of the center involved, the FDA will approve a biologic (i.e., issue a biologics license) only if it determines that the sponsor can continually produce a product that is “safe, pure, and potent.” The FDA bases this determination on information in the BLA about the biologic itself, as well as the proposed manufacturing process and facilities.
EXAMPLE 14.7
Biotech X makes and sells anticancer biologics.
Scientists at Biotech X develop new humanized monoclonal antibody BX1. BX1 is homologous with, and targets the same epitope as, trastuzumab (Herceptin). The Biotech X scientists also perform preclinical studies on BX1, which show its promise as a first-line treatment for breast cancer in humans.
Biotech X submits an IND to the FDA for BX1, an antibody that has never been used in humans. In the IND, Biotech X provides detailed information about (i) BX1’s breast cancer cell–specific toxicity in relevant human cell culture experiments, and (ii) BX1’s pharmacodynamic and pharmacokinetic properties in transgenic mouse models of human breast cancer.
Biotech X also provides BX1’s amino acid sequence and other physical properties such as known post-translational modifications. Importantly, Biotech X provides detailed information about the BX1-producing cells, cell banking, culturing reagents and conditions, and production facilities to be used. Also presented in the IND are details of Biotech X’s methods for testing the antibody for purity and structural and functional integrity.
The IND further proposes clinical trials, starting with a phase 1 study to demonstrate BX1’s safety in humans. Here, Biotech X specifies that this study will include a total of twenty patients with breast cancer within defined age ranges and having defined breast cancer types, defined disease stages, and defined treatment histories. The IND describes the proposed lyophilized BX1 formulation, pre-administration reconstitution procedure, intravenous administration route, and regimen for dose escalation and other safety studies. For phase 1, this regimen requires intravenously administering single and weekly BX1 doses ranging from 10 mg to 500 mg per subject.
Also included in the IND are other requisite types of information, such as information about the investigators and descriptions of observations and measurements that the investigators will make during the trial.
Thirty days after the FDA receives its IND, Biotech X begins its phase 1 trial of BX1.
The phase 1 trial data show that like trastuzumab, BX1 is well tolerated at the doses tested, and the maximum tolerated dose was not reached. These data also show that BX1’s pharmacokinetic profile is similar to that of trastuzumab.
In addition to establishing the pharmacokinetics and relative safety of BX1, the phase 1 study also yields clinical data consistent with BX1’s ability to treat breast cancer.
Based on the successful completion of its phase 1 study, Biotech X amends its IND to more accurately set forth the protocol for its phase 2 study. Biotech X then begins that study as proposed.
The phase 2 study involves one hundred patients. In relevant part, the investigators intravenously administer BX1 at an initial dose of 5 mg/kg as a ninety-minute intravenous infusion, followed for up to twenty-six weeks by a weekly dose of 2 mg/kg as a sixty-minute intravenous infusion (Regimen 1).
The phase 2 data show that like trastuzumab, BX1 causes an increased incidence of symptomatic myocardial dysfunction among patients receiving the candidate biologic as a single agent. However, this increase was only three- to four-fold in patients receiving the candidate biologic, as opposed to four- to six-fold in patients receiving trastuzumab. The trial data do not show any other adverse effects that are more severe than those resulting from trastuzumab treatment.
Based on the successful completion of its phase 2 study, Biotech X meets with the FDA to discuss the phase 2 results and proposed phase 3 study design. The company again amends its IND to finalize the phase 3 study protocol and files appropriate documents concerning its discussions with the FDA and the resulting changes to its clinical protocol. After amending its IND, Biotech X begins the proposed study, which is multicenter and involves five hundred patients. In relevant part, based on the phase 2 data, the investigators now administer BX1 at a reduced initial dose of 4 mg/kg as a ninety-minute intravenous infusion, followed for up to twenty-six weeks by a weekly dose of 2 mg/kg as a thirty-minute intravenous infusion (Regimen 2).
The phase 3 trial data show only a two- to three-fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving BX1 as a single agent. This is far lower than the three- to four-fold increase seen with Regimen 1. Meanwhile, Regimens 1 and 2 have comparable efficacies. The phase 3 data do not show any adverse effects more severe with Regimen 2 than those resulting from Regimen 1. Because of the size of the phase 3 study, these results are statistically significant.
Additionally, the phase 3 investigators determined that BX1 results in pulmonary toxicity less frequently than does trastuzumab. Thus, the phase 3 data reveal yet another advantage of BX1 over trastuzumab.
After successfully completing the phase 3 study, Biotech X attends a pre-BLA meeting with the FDA and then submits its BLA for BX1. In it, Biotech X sets forth the types of information it otherwise would were BX1 a small-molecule drug: for example, all preclinical data on BX1’s pharmacology and toxicology; all clinical data and their relevance to BX1’s pharmacokinetics, bioavailability, efficacy, and adverse effects; and its proposed labeling for BX1. Because BX1 is a biologic, however, Biotech X’s BLA also stresses BX1’s characteristics and precisely how and where Biotech X will manufacture this drug so that its safety, purity, and potency remain consistent over time.