The U.S. Food and Drug Administration (FDA) has rejected sacituzumab govitecan also known as IMMU-132, a novel, investigational, antibody-drug conjugate or ADC consisting of SN-38, the active metabolite of irinotecan, conjugated to a humanized monoclonal antibody targeting trophoblastic antigen-2 (Trop2), which is expressed in approximately 80% to 90% of breast cancers.
Triple-negative breast cancer
The investigational drug is designed for the treatment of patients with triple-negative breast cancer (TNBC) who have failed at least 2 prior therapies for metastatic disease.
About 15% of all diagnosed breast cancers is triple-negative breast cancer and, according to the American Cancer Society, the an annual incidence of the disease in the United States alone is estimated to be about 40,000 patients, with 20,000 diagnosed with metastatic TNBC, in the United States alone.
Triple-negative breast cancer does not express estrogen, progesterone or the HER2 receptor. As a result, the disease is insensitive to most of the available targeted therapies for breast cancer treatment, including HER2-directed therapies like trastuzumab (Herceptin®; Genentech/Roche), and endocrine therapies such as tamoxifen or the aromatase inhibitors.
“We believe in sacituzumab govitecan’s potential to be a viable treatment option for these patients,” said Michael Pehl, President and Chief Executive Officer of Immunomedics.
This believe was, in part, based on a Breakthrough Therapy Designation the company received in February 2016 and results from various clinical trials investigating the activity of sacituzumab govitecan in patients with advanced cancers. One of the trials, presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO), showed that sacituzumab govitecan, as a single agent demonstrated, had significant clinical activity in heavily pre-treated patients with HR-positive, HER-2-negative metastatic breast cancer and has a predictable and manageable safety profile.
However, regardless of the results of clinical results, on february 17, 2019 Immunimedics confirmed that it has received a Complete Response Letter from the FDA for the Biologics License Application in which the FDA rejected the drugs.
Although the FDA did not raise concerns about the safety or efficacy of sacituzumab govitecan, the disappointing outcome follows serious manufacturing problems identified in the FDA inspection between August 6 and 14, 2018.
“The issues related to approvability in the Complete Response Letter were exclusively focused on Chemistry, Manufacturing and Control matters and no new clinical or preclinical data need to be generated,” Pehl noted.
This investigation revealed that Immunomedics’s quality control unit at the company’s Morris Plains, New Jersey, drug substance manufacturing facility didn’t have the authority to investigate a February 2018 data integrity breach, which didn’t trigger a deviation. This breach included manipulated bioburden samples, misrepresentation of an integrity test procedure in the batch record, and backdating of batch records, such as dates of analytical results.
According to the FDA, Immunomedics did not give an assurance that samples and batch records from commercial batches it manufactured before the data integrity breach were not impacted by it, and the agency was unable to conduct a proper assessment.
As a result of the problems, the FDA cited Immunomedics for multiple violations. However, according to statements to investors in December 2018 made by the company, the identified problems for which the company has been penalized have been addressed and are now (completely) resolved.
“We are going to request a meeting with the FDA as soon as possible to gain a full understanding of the Agency’s requirements and timelines for approval and we will work closely with the FDA,” Pehl said.
“The goal [is to bring] this important medicine to patients as soon as possible,” he concluded.
The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation for STRO-001 for the treatment of multiple myeloma (MM).
In the United States, Orphan Drug Designation provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug.
STRO-001, which is being developed by Sutro Biopharmam, a clinical-stage drug discovery, development and manufacturing company, is a potential first-in-class antibody-drug conjugate or ADC targeting CD74, a type II transmembrane glycoprotein involved in the formation and transport of MHC class II protein which is highly expressed in B-cell malignancies such as multiple myeloma, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and other types of NH. 
“There is a growing need for new treatment options for patients with multiple myeloma,” commented Bill Newell, Sutro’s Chief Executive Officer.
“This Orphan Drug Designation is a great step towards advancing our uniquely designed STRO-001 that could bring new treatment options to patients in need.”
STRO-001 was developed with Sutro’s proprietary cell-free protein synthesis and site-specific conjugation platform, XpressCF+™, which facilitate precision design and rapid empirical optimization of ADCs.
The company’s technology platform is made possible by the separation, into an extract, of the cellular components required to produce proteins from the process of protein generation itself. The extract includes all the necessary biochemical components for energy production, transcription and translation and can be used to support cell-free biochemical protein synthesis by the addition of the specific DNA sequence for the desired protein. The process produces single proteins at g/L yields in 8-10 hours at any scale.
One of the benefits of Sutro’s technology is that it enables design and manufacture of a highly optimized single molecular species within the product, rather than the usual mixture of imprecisely conjugated antibodies that comprise an ADC development product made by conventional cell-based manufacturing platforms.
In addition, the platform helps accelerate discovery and development of potential first-in-class and best-in-class molecules through rapid and systematic evaluation of protein structure-activity relationships to create optimized homogeneous product candidates.
“STRO-001 was designed to directly target cancer cells to deliver a cytotoxic payload. Building upon our XpressCF+™ platform we plan to develop better options to treat tumors with greater precision,” Bill Newell explained.
Sutro’s proprietary and integrated cell-free protein synthesis and site-specific conjugation platform, XpressCF+™, led to the discovery of STRO-001 and STRO-002, Sutro’s first two internally-developed antibody drug conjugates
STRO-001 is currently being studied in a Phase I clinical trial enrolling separate dose escalation cohorts for myeloma and B-cell lymphoma.
The second drug being developed using Sutro’s proprietary platform, STRO-002, is a potentially best-in-class ADC targeting folate receptor alpha, a cell-surface protein highly expressed in gynecological cancers.
The United States Food and Drug Administration (FDA) has lifted the partial clinical hold on the Phase I study of XMT-1522, a Dolaflexin® Antibody-drug Conjugate (ADC) targeting HER2-expressing tumors being developed by Mersana Therapeutics.
XMT-1522 contains a proprietary HER2 antibody which is conjugated with Mersana’s Dolaflexin platform – a Fleximer polymer linked with a novel, proprietary, auristatin payload. The investigational agent provides a drug load of approximately 12 molecules per antibody, specifically designed to improve potency while simultaneously increasing tolerability.
Lower levels of HER2-expression
XMT-1522 has the potential to extend HER2-targeted therapy beyond the current HER2-positive populations into patients with lower levels of HER2 expression. The Phase I protocol will evaluate XMT-1522 in patients with advanced HER2-positive breast and gastric cancer, as well as advanced breast cancer with low HER2 expression and non-small cell lung cancer (NSCLC). More information on the ongoing Phase 1 clinical trial can be found at clinicaltrials.gov.
Changes to the protocol
Mersana and the FDA reached alignment on changes to the protocol. These changes include increased monitoring as well as the exclusion of patients with advanced hepatic impairment. Although XMT-1536, another investigational agent being developed by Mersana,was not subject to a clinical hold, the company decided to implement similar modifications to the XMT-1536 protocol.
XMT-1536 is Mersana’s highly potent immunoconjugate targeting the sodium-dependent phosphate transport protein (NaPi2b) comprised of an average of 10-15 DolaLock™ payload molecules conjugated to XMT-1535, a proprietary humanized anti-NaPi2b antibody, via the Dolaflexin ADC platform.
In addition to the changes in the protocol, alternative dosing regimens will be evaluated for both clinical trials.
The XMT-1522 trial will begin with a once-every-four-week dose regimen. This dosing regimen has already been implemented in the XMT-1536 trial at previously explored dose levels in order to enable a comparison of relevant doses and their impact on the safety, efficacy and PK profile of the drug candidate. The company may evaluate additional regimens as well. Data on XMT-1536 is expected in the first half of 2019.
“We are excited to resume enrollment on the XMT-1522 trial and to work with investigators to explore the full potential of both promising drug candidates in the solid tumor setting,” said Anna Protopapas, Chief Executive Officer of Mersana.
In our globalized world, human pharmaceutical residues and traces of other (chemical) down-the-drain contaminants have become an environmental concern. Following the detection of (pharmaceutical) drug residues in drinking and surface waters , regulatory agencies around the world, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have developed detailed guidance on how pharmaceutical products should be assessed for possible adverse environmental effects.
Hence, an Environmental Risk Assessment or ERA is required as part of the clinical development, regulatory submission and marketing authorization of pharmaceuticals. This is mandatory for drugs both for the treatment of human diseases as well as veterinary use.
Using fate, exposure and effects data, an environmental risk assessment or ERA evaluates the potential risk of (new) medicinal compounds and the environmental impact they cause.
Despite the available guidance from regulatory agencies, regulatory policy is complex, and a number of aspects related to ERA remain unclear because they are not yet well defined. Furthermore, the specific requirements are not always straightforward. Moreover, while some types of chemicals are exempt (e.g., vitamins, electrolytes, peptides, proteins), such exemption may be overruled when a specific mode of action (MOA) involves endocrine disruption and modulation.
In this white paper, which focuses on human pharmaceuticals rather than veterinary pharmaceuticals, the author reviews topics ranging from regulations and environmental chemistry to exposure analysis and environmental toxicology. He also addresses key aspects of an ERA.
The effective functioning of a modern, healthy society increasingly demands developing novel therapeutic agents for the treatment of human and veterinary disease as well as the new and emerging technologies that form the foundation for advancement. A proper understanding of environmental health and safety risks that may have been introduced into the environment as part of developing these new medicines is an important part of this process.
To understand these risks, Environmental Risks Assessments or ERAs are designed to systematically organize, evaluate and understand relevant scientific information. The purpose of such assessment is to ascertain if, and with what likelihood, individuals are directly or indirectly exposed to (novel) medicinal compounds, (bio) pharmaceutical products or active pharmaceutical ingredients in our immediate environment, as well as the consequences of such exposure. The information can then be used to assess if the use of these agents may result in unintended health-related impairment or harm as the result of such exposure, as well as the impact these agents may have on a globalized world. 
Exposure may occur if humans come into contact with (novel) medicinal compounds, (bio) pharmaceutical products or active pharmaceutical ingredients. And while therapeutic agents may be intended to cause some measure of harm – for example, chemotherapeutic agents in the treatment of patients with various forms of cancer designed to “kill” malignant cells – unintended environmental exposure may, in turn, cause unintended serious adverse events. In many cases, such exposure may be limited to trace levels of the active pharmaceutical ingredient.
Over the past 30 years, the impact of such exposure, as well as its implications, have become clearer. Because early analytical equipment was not very sensitive, traces of (novel) therapeutic and medicinal compounds, (bio) pharmaceuticals and active pharmaceutical ingredients were not easily detected in the environment until the 1990s. The result was that the impact of these agents in the environment was generally considered nonexistent and unimportant.
However, since the late 1940s, scientists have been aware of the potential that a variety of chemicals are able to mimic endogenous estrogens and androgens. 
The first accounts indicating that hormones were not completely eliminated from municipal sewage, wastewater and surface water were not published until 1965, by scientists at Harvard University,  and it was not until 1970 that scientists, concerned with wastewater treatment, probed to what extent steroids are biodegradable, because hormones are physiologically active in very small amounts. 
However, the first report specifically addressing the discharge of medicinal compounds, pharmaceutical agents or active pharmaceutical ingredients into the environment was published in 1977 by scientists from the University of Kansas. 
Despite these and many other early findings, the subject of medicinal compounds such as steroids and other pharmaceutical residues in wastewater did not gain significant attention until the 1990s, when the occurrence of hermaphroditic fish was linked to natural and synthetic steroid hormones in wastewater. 
In numerous studies and reports, researchers hypothesized and confirmed that effluent discharge in the aquatic environment, such as municipal sewage, wastewater systems as well as surface waters, contained either a substance or (multiple) substances, including natural and synthetic hormones, that are estrogenic to fish, affecting their reproductive systems. 
In time, scientists confirmed that these adverse effects, and implications of endocrine disruption and modulation, were caused by residues of estrogenic human pharmaceuticals. 
After discovering hermaphroditic fish in and near water-treatment facilities, scientists identifying the estrogenic compounds that were most likely associated with this occurrence confirmed that substances such as ethynylestradiol, originating from pharmaceutical use, generated a similar effect in caged fish exposed to levels as low as 1 to 10 ng 1−1 and that positive responses may even arise at 0.1 to 0.5 ng 1−1. 
Although it was now recognized that the therapeutic agent or active pharmaceutical ingredient itself was biologically active, experts generally believed that there was only a limited environmental impact during manufacturing; and because these therapeutic agents were only manufactured in relatively small amounts, they were not concerned about the potential environmental risk of pharmaceutical residues and trace contaminants. 
Today, with pharmacotherapy a common part of our daily life, many concerned citizens realize that pharmaceutical residues and trace contaminants may represent an increased environmental risk with potential consequence for human and animal health. 
And although the concentrations of these residues rarely exceed the level of parts per billion (ppb), limiting acute toxicity, the emergence of these residues and traces in the environment fundamentally changed the way we look at the (potential) risk of these active pharmaceutical ingredients in the ecosystem. 
But regulators have also come to understand that environmental risk assessment developed for non-medicinal chemical containment cannot necessarily be applied to (novel) medicinal compounds, (bio) pharmaceutical products or active pharmaceutical ingredients. They understand that protecting the environment, while at the same time improving human and animal health, requires a better understanding of how to protect the environment (the ecosystem) as well as the active pharmaceutical ingredient in its own regulated environment.
5.0 Value for society
The issue of medicinal compounds, (bio) pharmaceutical agents and active pharmaceutical ingredients in our environment is complex. This complexity is, in part, derived from the medicinal value of these compounds and the general acceptance that patient use – and therefore the excretion of active pharmaceutical ingredients into the environment and, as a result, the potential of harmful effects to the ecosystem and human health – rather than other methods of release, is the primary reason why we find traces of these agents in our environment. 
There is no doubt that modern medicines developed by research-based pharmaceutical companies have brought tremendous value. For example, the development of antibiotics generated enormous gains in public health through the prevention and treatment of bacterial infections. In the 20th century, the use of antibiotics aided the unprecedented doubling of the human life span. 
Before the development of insulin in the late 1920s and early 1930s, people diagnosed with diabetes (type 1) were not expected to survive. In 1922, children with diabetes rarely lived a year after diagnosis. Five percent of adults died within two years, and less than 20% lived more than 10 years. But since insulin became available, the drug has become a daily routine for people with diabetes, creating a real survival benefit and making the difference between life and death. 
Pharmaceutical agents have also drastically impacted social life. The introduction of the pill in the early 1960s, for example, affected women’s health, fertility trends, laws and policies, religion, interpersonal relations, family roles, women’s careers, gender relations and premarital sexual practices, offering a host of contraceptive and non-contraceptive health benefits. 
It can be said that the emergence of the women’s rights movement of the late 1960s and 1970s is directly related to the availability of the pill and the control over fertility it enabled: It allowed women to make personal choices about life, family and work. 
The development of novel targeted anticancer agents, including antibody-drug conjugates or ADCs, have resulted in a new way of treating cancer and hematological malignancies with fewer adverse events, longer survival and better quality of life (QoL).
In the end, the economic impact of pharmaceutical agents, some hailed as true miracles, has been remarkable, contributing to our ability to cure and manage (human) disease and allowing people to live longer, healthier lives.
At the same time, the (clinical) use of (novel) medicinal or (bio) pharmaceutical agents and their underlying active ingredients can also harbor a number of risks for the environment.
6.0 Understanding environmental risk
In the development of novel therapeutic agents, intensive pre-clinical investigations yield a vast amount pharmacological and toxicological data. During the discovery and (early) development of therapeutic agents, researchers are paying close attention to target specificity and pathways to understand how an innovative drug compound may have beneficial efficacy in the treatment of human or veterinary diseases. Because adverse events are undesirable, drug developers often focus on therapeutics with a well-understood mechanism of action (MOA) and low toxicity (often measured in ng/L). 
As a result, only a small number of pharmaceuticals will be classified as highly and acutely toxic, requiring new approaches to identify pharmaceutical agents in robust environmental hazard and risk assessments. 
7.0 Pharmaceutical risk assessment
While non-medicinal and chemical entities produced in significant commercial quantities require an environmental risk assessment based on a minimum set of hazard data to assess and manage risks to humans and the environment, such an approach does not necessarily apply to (novel) therapeutic agents. One reason is that the health and wellbeing of humans should never be assessed and managed on the basis of risk alone. Regulators generally require drug developers or sponsors to undertake a comprehensive assessment of the potential risks and benefits of a proposed therapeutic agent, which may demonstrate significant risk to the patient. However, these risks are largely offset by the medicinal benefits of such agents.
Regulators around the world require a systematic and transparent assessment of the (potential) of environmental risk in addition to a (novel) medicinal agent’s quality, safety and efficacy, and relevance as part of regulatory decision-making. 
8.0 Environmental risk and regulatory requirements in the United States
The legal mandate of protecting the environment in the United States consists of the National Environmental Policy Act of 1969 (NEPA), which requires all federal agencies to assess the environmental impact of their actions and the impact on the environment, and the Federal Food, Drug and Cosmetic Act (FFDCA) of 1938 (amended in 1976).
This legal framework further determines that the regulation of pharmaceuticals in the environment is the responsibility of the United States Environmental Protection Agency or EPA and the United States Food and Drug Administration (FDA), which is required to consider the environmental impact of approving novel therapeutic agents and biologics applications as an integral part of the regulatory process.
The FDA has required environmental risk assessments for (novel) medicinal compounds, (bio) pharmaceutical agents and active pharmaceutical ingredients for veterinary use (since 1980) as well as the treatment of human diseases (since 1998).
As such, the FDA regulations in 21 CFR part 25 identify which Pharmaceutical Environmental Risk Assessment or PERA is required as part of a New Drug Application or NDA, abbreviated application, Investigational New Drug application or IND. 
The same regulations (21 CFR 25.30 or 25.31) identify categorical exclusions for a number of products and product categories – including vitamins, electrolytes, peptides, proteins, etc. – that do not require the preparation of an environmental risk assessment or ERA because, as a class, these agents, individually or cumulatively, do not significantly affect the quality of the (human) environment.
In addition, and in contrast to the categorical exclusion, these regulations also identify cases when such an exemption may be overruled as the result of a specific mode of action (MOA) involving endocrine disruption and modulation. 
9.0 Required ERA
Under the applicable regulations, NDAs, abbreviated applications and supplements to such applications do not qualify for a categorical exclusion if the FDA’s approval of the application results in an increased use of the active moiety or active pharmaceutical ingredient, as a result of higher dose levels, use of a longer duration, for a different indication than was previously approved, or if the medicinal agent or drug is a new molecular entity and the estimated concentration of the active therapeutic agent at the time of entry into the aquatic environment is expected to be 1 part per billion (ppb) or greater.
Furthermore, a categorical exclusion is not applicable when approval of an application results in a significantly altered concentration or distribution of a (novel) therapeutic agent, the active pharmaceutical ingredient, its metabolites or degradation products in the environment.
Regulations also refer to so-called extraordinary circumstances (stated in 21 CFR 25.21 and 40 CFR 1508.4) where a categorical exclusion does not exist. This may be the case when a specific product significantly affects the quality of the (human) environment and the available data establishes that there is a potential for serious harm. Such environmental harm may go beyond toxicity and may include lasting effects on ecological community dynamics. Hence, it includes adverse effects on species included in the United States Endangered Species Act (ESA) as well as other federal laws and international treaties to which the United States is a party. In these cases, considered extraordinary circumstances, an environmental risk assessment is required unless there are specific exemptions relating to the active pharmaceutical ingredient.
10.0 Naturally Occurring Substances
Based on the current regulations, a drug or biologic may be considered to be a “naturally occurring” substance if it comes from a natural source or is the result of a biological process. This applies even if such a product is chemically synthesized. The regulators consider the form in which an active ingredient or active pharmaceutical agent exists in the environment to determine if a medicinal compound or biologic is a naturally occurring substance. Biological and (bio) pharmaceutical compounds are also evaluated in this way.
According to the Guidance for Industry, a protein or DNA containing naturally occurring amino acids or nucleosides with a sequence different from that of a naturally occurring substance will, after consideration of metabolism, generally qualify as a naturally occurring substance. The same principle applies to synthetic peptides and oligonucleotides as well as living and dead cells and organisms. 
11.0 Preparing an Environmental Risk Assessment
If an environmental risk assessment is required, the FDA requires drug developers and/or sponsors to focus on characterizing the fate and effects of the active pharmaceutical ingredient in the environment as laid out in the Guidance for Industry, Environmental Assessment of Human Drugs and Biologics Applications (1998). 
This is generally the case if the estimated concentration of the active pharmaceutical ingredient being considered reaches, at the point of entry into the aquatic environment, a concentration ≥1 PPB; significantly alters the concentration or distribution of a naturally occurring substance, its metabolites or degradation products in the environment; or, based on available data, it can be expected that an increase of the level of exposure may, potentially, lead to serious harm to the environment. 
To guarantee that satisfactory information is available, the 1998 Guidance for Industry lays out a tiered approach for toxicity testing to be included in an environmental risk assessment. [Figure I] 
Furthermore, if potential adverse environmental impacts are identified, the environmental risk assessment should, in accordance with 21 CFR 25.40(a), include a discussion of reasonable alternatives designed to offer less environmental risk or mitigating actions that lower the environmental risk.
12.0 A Tiered Approach
The fate and effects testing is based on a tiered approach:
12.1 Tier 1
This step does not require acute ecotoxicity testing to be performed if the EC50 or LC50 divided by the maximum expected environmental concentration (MEEC) is ≥1,000, unless sublethal effects are observed at the MEEC. If sublethal effects are observed, chronic testing as indicated in tier 3 is required. 
12.2 Tier 2
In this step, acute ecotoxicity testing is required to be performed on a minimum of aquatic and/or terrestrial organisms. In this phase, acute ecotoxicity testing includes a fish acute toxicity test, an aquatic invertebrate acute toxicity test and analgal species bioassay.
Similar to tier 1, tier 2 does not require acute ecotoxicity testing to be performed if the EC50 or LC50 for the most sensitive organisms included in the base test, divided by the maximum expected environmental concentration (MEEC) is, in this tier, ≥100, unless sublethal effects are observed at the MEEC. However, as in the case of tier 1, if sublethal effects are observed, chronic testing as indicated in tier 3 is required. 
12.3 Tier 3
This tier requires chronic toxicity testing if the active pharmaceutical ingredient has the potential to bioaccumulate or bioconcentrate, or if such testing is required based on tier 1 or tier 2 test results. 
13.0 Bioaccumulation and Bioconcentration
Bioaccumulation and bioconcentration are complex and dynamic processes depending on the availability, persistence and physical/chemical properties of an active pharmaceutical ingredient in the environment. 
Bioaccumulation and bioconcentration refer to an increase in the concentration of the active pharmaceutical ingredient in a biological organism over time, compared with the concentration in the environment. In general, compounds accumulate in living organisms any time they are taken up and stored faster than they are metabolized or excreted. The understanding of this dynamic process is of key importance in protecting human beings and other organisms from the adverse effects of exposure to a (novel) medicinal compound, (bio) pharmaceutical agent or active pharmaceutical ingredient, and it is a critical consideration in the regulatory process. 
According to the definition in the Guidance for Industry, active pharmaceutical ingredients are generally not very lipophilic and are, in comparison to industrial chemicals, produced in relatively low quantities. Furthermore, the majority of active pharmaceutical ingredients generally metabolize to Slow Reacting Substances or SRSs that are more polar, less toxic and less pharmaceutically active than the original parent compound. This suggests a low potential for bioaccumulation or bioconcentration. 
Following a proper understanding of this process, tier 3 chronic toxicity testing is required if an active pharmaceutical ingredient has the potential to bioaccumulate or bioconcentrate. A primary indicator is the octanol/water partition coefficient (Kow). If, for example, the logarithm of the octanol/water partition coefficient (Kow) is high, the active pharmaceutical ingredient tends to be lipophilic. If the coefficient is ≥3.5 under relevant environmental conditions, such as a pH of 7, chronic toxicity testing is required.
Tier 3 does not require further testing if the EC50 or LC50 divided by the maximum expected environmental concentration (MEEC) is ≥10, unless sublethal effects are observed at the MEEC.
In accordance with the Guidance for Industry, a drug developer or sponsor should include a summary discussion of the environmental fate and effect of the active pharmaceutical ingredient in an environmental risk assessment. The environmental risk assessment should also include a discussion of the affected aquatic, terrestrial or atmospheric environments. 
14.0 Special Consideration: Environmental Impact Statement
Following the filing of an environmental risk assessment for gene therapies, vectored vaccines and related recombinant viral or microbial products, the FDA will evaluate the information and, based on the submitted data, determine whether the proposed (novel) medicinal compound, (bio) pharmaceutical agent or active pharmaceutical ingredient may significantly affect the environment and if an Environmental Impact Statement (EIS) is required. According to 21 CFR 25.52, if an EIS is required, it will be available at the time the product is approved. Furthermore, if required, an EIS includes, according to 40 CFR 1502.1, a fair discussion of the environmental impact as well as information to help decision-makers and the public find reasonable alternatives that help in avoiding or minimizing adverse impacts or enhance environmental quality. 
However, if the FDA determines that an EIS is not required, a Finding of No Significant Impact (FONSI) will, according to 21 CFR 25.41(a), explain why this is not required. This statement will include either the environmental risk assessment or a summary as well as reference to underlying documents supporting the decision. 
15.0 European requirements
In Europe, environmental risk assessments were, in accordance EU Directive 92/18/EEC and the corresponding note for guidance issued by the European Medicines Agency (EMA), first required for (novel) medicinal agents for veterinary use in 1998. The requirement for an environmental risk assessment for (novel) medicinal agents, (bio) pharmaceuticals and active pharmaceutical ingredients for the treatment of human disease was first described in 2001 in Directive 2001/83/EC.
Subsequent to an initial guiding document published in January 2005, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) issued its final guidance for the assessment of environmental risk of medicinal products for human use in 2006. 
After the discovery of pharmaceutical residues and trace contaminants in the environment, regulators in the European Union require that an application for marketing authorization of a (novel) medicinal or (bio) pharmaceutical agent is accompanied by an environmental risk assessment.
This requirement is spelled out in the revised European Framework Directive relating to medicinal products for human use. It applies for new registrations as well as repeat registrations for the same medicinal agent if the approval of such an extension or application leads to the risk of increased environmental exposure.
In Europe, the objective of the environmental risk assessment is to evaluate, in a step-wise, phased procedure, and as part of the Centralized Procedure by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), the potential environmental risk of (novel) medicinal compounds, (bio) pharmaceutical agents and/or active pharmaceutical ingredients. Such an assessment will be executed on a case-by-case basis.
16.0 Phase I
In this process, Phase I estimates the exposure of the environment to the drug substance and is only focused on the active pharmaceutical ingredient or drug substance/active moiety, irrespective of the intended route of administration, pharmaceutical form, metabolism and excretion.
This phase excludes amino acids, proteins, peptides, carbohydrates, lipids, electrolytes, vaccines and herbal medicines, because regulators believe that these biologically derived products are unlikely to present a significant risk to the environment. 
The exemption for these biologically derived biopharmaceuticals is generally interpreted as an exemption for all biopharmaceutical agents manufactured via live organisms and that have an active ingredient that is biological in nature. 
Yet, not all biologically derived biopharmaceuticals are (easily) biodegradable, and scientists have detected modified natural products, including plasmids, in the environment. Furthermore, some protein structures, including prions, are very environmentally stable and resistant to degradation, allowing them to persist in the environment.  Hence, this approach requires future scientific justification.
In Phase I, following the directions included in the European Chemicals Bureau (2003) Technical Guidance Document, an active pharmaceutical ingredient or drug substance/active moiety with a logKow >4.5 requires further screening for persistence, bioaccumulation and toxicity, or a PBT assessment.
For example, based on the OSPAR Convention and REACH Technical Guidance, highly lipophilic agents and endocrine disruptors are referred to PBT assessments.
Phase I also includes the calculation of the Predicted Environmental Concentration or PEC of active pharmaceutical ingredients, which, in this phase, is restricted to the aquatic environment, and a so-called “action limit” requiring additional screening.
The “action limit” threshold for the PEC in surface water (PECsurface water), for example, is calculated by using the daily dose of an active pharmaceutical ingredient, the default values for wastewater production per capita, and the estimated sale and/or distribution of the active pharmaceutical ingredient if there is evidence of metabolism and no biodegradation or retention following sewage treatment is observed.
17.0 Phase II
Phase II, divided into two parts, tier A and tier B, assesses the fate and effects of novel medicinal compounds, (bio) pharmaceutical agents or active pharmaceutical ingredients in the environment.
Following the assessment of the PEC/PNEC ratio based on relevant environmental fate and effects data (Phase IIA), further testing may be needed to refine PEC and PNEC values in phase II tier B. A PEC/PNEC ratio of This process helps regulators to evaluate potential adverse effects independently of the benefit of the (novel) medicinal compound, (bio) pharmaceutical agent or active pharmaceutical ingredient, or the direct or indirect impact on the environment.
Stage in regulatory evaluation
Stage in risk assessment
TEST / DATA REQUIREMENT
Estimation of exposure
Consumption data, logKow
Phase II Tier A
Initial prediction of risk
Base set aquatic toxicology and fate
Phase II Tier B
Substance and compartment-specific refinement and risk assessment
Extended data set on emission, fate and effects
Table 1: The Phased Approach in Environmental Risk Assessment in Europe
18.0 Outcome of fate and effects analysis
In all cases, the medicinal benefit for patients has relative precedence over environmental risks. This means that even in the case of an unacceptable (residual) environmental risk caused by a novel medicinal compound, pharmaceutical agent or active pharmaceutical ingredient, after third-tier considerations, prohibition of a new active pharmaceutical ingredient is not taken into consideration.
If European regulators determine that the possibility of environmental risk cannot be excluded, mitigating, precautionary and safety measures may require the development of specific labeling designed to address the potential risk, as well as adding adequate information in the Summary of Product Characteristics (SPC), Package Leaflet (PL) for patient use, product storage and disposal. The information on the label, SPC and PL should also include information on how to minimize the discharge of the product into the environment and how to deal with disposal of unused product, such as in the case of shelf-life expiration.
In extreme cases, a recommendation may be included for restricted in-hospital or in-surgery administration under supervision only, a recommendation for environmental analytical monitoring, or a requirement for ecological field studies.  
19.0 Combined effects
Often overlooked by regulators is the fact that the regulatory frameworks such as the European REACH Regulation, the Water Framework Directive (WFD) and the Marine Strategy Framework Directive (MSFD) mainly focus on toxicity assessment of individual chemicals or active pharmaceutical ingredients.
This poses a problem for the proper execution of environmental risk assessments and regulation because the effect of contaminant mixtures with multiple chemical agents and active pharmaceutical ingredients, irregardless of their source, is a matter of growing, and recognized, scientific concern. 
To solve this problem, scientists are working on experimental, modeling and predictive environmental risk assessment approaches using combined effect data, the involvement of biomarkers to characterize Mode of Action, and toxicity pathways and efforts to identify relevant risk scenarios related to combined effects of pharmaceutical residues, trace contaminants as well as non-medicinal (industrial) chemicals. 
20.0 International harmonization
Created in the 1990s, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was set up as an agreement between the European Union, the United States and Japan to harmonize different regional and national requirements for registering pharmaceutical agents in order to reduce the need to duplicate testing during the research and development phase of (novel) medicinal compounds, (bio) pharmaceutical agents and active pharmaceutical ingredients. However, to date, and partly as a result of the overlying differences in regulations and directives, environmental risk assessments have, so far, not been included in the harmonization procedures. 
In contrast, the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products, or VICH, similar to the ICH a trilateral set up in 1996 between the European Union, the Unites States and Japan, does include the assessment of ecotoxicity and the evaluation of environmental impact of veterinary medicinal products.
The VICH guideline, intended to provide a common basis for an Environmental Impact Assessment or EIA, offers guidance for the use of a single set of environmental fate and toxicity data and is designed to guide scientists to secure the type of information needed to protect the environment. The guideline, published in 2004 and recommended for implementation in 2005, was developed as a scientifically objective tool to help scientists and regulators extract the maximum amount of information from studies to achieve an understanding of the potential (risk) of specific Veterinary Medicinal Products to the environment. 
21.0 Impact of Environmental Risk Assessment
Although an environmental risk assessment is part of the regulatory approval and marketing authorization process in both the United States and Europe, the actual impact can be different.
In Europe, an adverse environmental risk assessment for (novel) medical compounds, (bio) pharmaceutical agents or active pharmaceutical ingredients for human use does not impact or influence the marketing approval application. EU Directive 2004/27/EC/Paragraph 18 stipulates that the environmental impact should be assessed and, on a case-by-case basis, specific arrangements to limit it should be envisaged. In any event, the impact should not lead to refusal of a marketing authorization.
However, a parallel directive pertaining to veterinary medicine, as laid out in EU Directive 2009/9/EC, stipulates that, in the case of veterinary medicine, an environmental impact assessment should be conducted to assess the potential harmful effects and the kind of harm the use of such a product may cause to the environment, as well as to identify any precautionary measures that may be necessary to reduce such risk.
Furthermore, the directive requires that, in the case of live vaccine strains which may be zoonotic, the risk to humans also needs to be assessed. In the case of veterinary medicine, an environmental impact assessment is part of the overall risk-benefit assessment, and, in the case of a negative result, may potentially lead to a refusal to approve the medicinal compound, (bio) pharmaceutical agent or active pharmaceutical ingredient.
In the United States, the FDA has eliminated environmental assessment requirements for certain types of veterinary drugs when they are not expected to significantly affect the environment. However, a negative assessment, based on unacceptable risk to “food” or “non-food” animals, can result in a refusal of a New Animal Drug Application (NADA) or a Supplemental New Animal Drug Application (SNADA). 
The central questions in the development of (novel) medicinal compounds, (bio) pharmaceutical products or active pharmaceutical ingredients for the treatment of human and veterinary disease is whether a novel agent will have an effect on the environment.
Regulators around the world, including in the United States and Europe, follow different assessment methodologies to ascertain these risks. However, all regulators use fate, exposure and effects data to help them understand if a (novel) medicinal compound, (bio) pharmaceutical agent or active pharmaceutical ingredient harbors a potential environmental risk, causing potential harmful effects on the ecosystem, and how this impacts human and veterinary health.
In all cases, environmental risk assessments are carried out based on scientifically sound premises, relying on established, accepted and universally known facts.
Overall, environmental risk assessments are useful analytical tools, providing critical information contributing to public health, as well as key instruments in guiding environmental policy decision-making.
As such, they play a key role in building a better, healthier world.
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Thius week, following the World ADC Summit in Berlin, Germany, Novasep, a leading supplier of services and technologies for the life sciences industry, announced that its new €11M bioconjugation facility is now operational. The greenfield facility was erected within 20 months on the company’s Le Mans site in France.
In its Le Mans facility Novasep produces highly potent cytotoxic active pharmaceutical ingredients (HPAPI) and registered advanced intermediates for commercial or clinical development use. The site also offers regulatory and containment evaluation support. It produces paclitaxel, for which Novasep holds a valid Drug Master File and a European CEP (Certificate of Suitability). However, the site is renowned for antibody-drug conjugate or ADC payload production services.
The new, 2,000m2 facility features two flexible GMP production suites equipped with 10L to 400L vessels to support both clinical and commercial manufacturing of antibody-drug conjugates. The stand-alone facility is purpose-built and offers R&D services, QC and scale-up laboratories.
Over the last decade, Novasep has become a leading contract service provider in the ADC arena and the the new facility completes the company’s ADC manufacturing platform already featuring commercial scale production capabilities of cytotoxic payloads, chemical linkers and monoclonal antibody.
“We designed the facility to ensure smooth and robust scale-ups and address the ADC-specific analytical and process challenges.” Rachel de Luca, General Manager of Le Mans site said.
“Our team has a long experience in applying DoE to chemical synthesis and bioprocessing and efficiently develop conjugation and purification steps on a wide range of ADC platforms. Furthermore, the site has established good manufacturing practices meeting the Quality and SHE standards applied to the production of anti-cancer compounds, confirmed by a long track of successful FDA inspections,” De Luca added.
Antibody-drug conjugates are particularly complex to produce. This is in part because they are composed of a biological part – the monoclonal antibody, and a chemical part – the linker and the highly potent cytotoxic payload. Bioconjugation is the critical process step where both parts are assembled.
Although only two drugs have reached the market so far (brentuximab vedotion and ado-trastuzumab emtansine), the pipeline of ADC-based drugs in development is rich and promising. Many research platforms are being developed to control and improve further the activity of ADC drugs through alternative strategies of linkage, site specificity and new payloads. More generally, this approach addresses the patients’ demand for more targeted therapies having lower side effects.
“We are delighted to inaugurate this new unit which reflects Novasep’s strong know-how and expertise. Our Group continues to strengthen its position and pursue its investment strategy to delivering service excellence to its worldwide clients, at the forefront of innovative therapies which can change the life of patients,” noted Michel Spagnol, Ph.D, Chief Executive Officer and Chairman of Novasep.
Quality Assurance: FDA’s
In addition to the facility in Le Mans, Novasep’s has established facilities in Mourenx, France where operates the world’s largest chromatography plant dedicated to the pharmaceutical industry, in Leverkusen, Germany and in Shanghai, China.
In December 2016 the company’s custom manufacturing facilities in France (Mourenx and Le Mans) and in Germany (Leverkusen) each individually passed the general inspection process of the U.S. Food and Drug Administration (FDA) free of any 483 form. This means that in each case the FDA inspection confirmed that commercial APIs produced at each site are suitable for drugs marketed in the United States.
“This success has been made possible by the day-to-day good practices adopted by every
colleague involved in operations. The robust system implemented by Novasep’s quality assurance
team ensures these high standards,” explained Jean-Claude Romain, VP quality at Novasep.
“These three successful inspections reward this long-term teamwork and commitment.”
All products of the creative process are a reflection of the individual makeup of the inventors. A painting by Mark Rothko looks like a Rothko painting. A symphony by Wolfgang Amadeus Mozart does not sound like the works of other composers. A Harry Potter story is will never be confused with The Hardy Boys or Nancy Drew. Steve Jobs made sure that no one has trouble distinguishing an Apple computer from a PC. Beverly Sills, the opera soprano, was world renown not only because of her musical skills and technical mastery, but because her voice had a very distinctive and pleasant timbre.
It should not be surprising therefore that drugs, which are also products of human creativity and ingenuity, reflect the character of the people who discover them.
Soil microorganisms have been explored as sources for novel drugs ever since 1928, the year when Alexander Fleming took note of an odd fungal contaminant in one of his experiments that turned out to produce penicillin. Soon virtually all common soil microorganisms had been screened for the production of clinically valuable yielding the antibiotics we typically rely on today: penicillins, cephalosporins, tetracycline, erythromycin etc. But by the 1980’s new antibiotics were getting harder and harder to find and workers began pursuing the idea that microbes growing in exotic places and exotic ecosystems would likely be the best sources to produce unusual and novel therapeutic leads. To encourage their employees to prospect for such microbes, most pharmaceutical research laboratories instituted the practice of “soil days”. The idea was that, if employees who went to unusual places on their vacations were willing to collect a few dozen soil samples while there, these employees would be awarded a “soil day”, a free day of extra vacation time.
It was a great deal for both parties. Collecting the soil samples was trivial, basically bending down and scooping a tablespoon of dirt into a tiny zip lock bag. The employee got a vacation day for minimal work and the pharmaceutical company gained access to some exotic samples. I did it myself. One year, when my spouse and I went on a hiking trip to Switzerland, I took a soil kit with me and picked up samples whenever we stopped at what looked to be an interesting place. One day we were hiking along the shore of an alpine lake and I noticed a beach with very fine powdery off white sand. It looked unusual so I bent down and scooped some up.
I didn’t think about this sample again until we were going through customs at Newark Airport. It’s against the law for individuals to bring food, farm products and soil samples into the United States, but you can import soils with a special permit. I was always scrupulous to make sure that I had my permit in the collecting kit before I left the country. So when the customs people looked at my luggage I had no worries, at least until the official started to look very suspiciously at my little bag of fine white powder. I whipped out my permit, but I think the customs man was not completely reassured until he saw that, along with my little bag of white powder, there were dozens of similar zip lock bags with contents ranging in appearance from simple garden dirt to dried mud and slimy pond muck. I also think my saying that I was hoping that one of these samples might lead to a novel treatment for AIDS related infections helped. He let us in through customs and I went right to lab where we found that my samples, collected with much hope and expectation, produced zero.
In the mid 1980’s a Lederle Lab scientist was on vacation in Texas in and took a chalky soil sample from an area near the town of Kerrville that the locals call the “calichi pits”. Back in the lab a strain of the Actinomycete bacteria, Micromonospora echinospora, was isolated from this soil sample and was found to produce a novel antibiotic later named calicheamicin . Calicheamicin is fabulously potent. The good news was that only a couple of calicheamicin molecules could easily kill a cancer cell (almost totally unheard of in efficacy and a thousand times more potent than some of the best clinical antitumor drugs, like adriamycin). The bad news was that only a couple of calicheamicin molecules could also easily kill a normal cell. In fact, calicheamicin kills everything it touches: bacteria, fungi and viruses, eukaryotic cells and eukaryotic organisms like mice and people.
Studies on calicheamicin by George Ellestad and Nada Zein, who among other scientists at at Lederle Laboratories*, showed why calicheamicin was so fabulously potent: it had a highly unusual mode of action . Calicheamicin acts as a “chemical nuclease”. Calicheamicin is similar to an enzyme (it’s really a chemical catalyst); it is able to repeatedly bind to DNA and make double strand breaks. Exposure to just a few molecules of calichaemicin can chop an entire genome into hamburger. But this finding also raised a question: how is the Actinomycete bacterium that produces calicheamicin is able to resist its toxicity? That question was answered by studies in the early 2000’s , which showed that Micromonospora echinospora produces a protective protein called CalC. Calichaemicin tightly binds to CalC, which leads to the destruction of both the CalC protein and the bound calichaemicin. As a result, any molecules of calichaemicin that remain within the producing organism are rapidly destroyed before they can do any damage.
The therapeutic goal for calicheamicin was therefore to devise some sort of guided missile that could selectively deliver lethal calicheamicin to cancer cells. This was a proven concept. One hundred years earlier the German scientist, Paul Ehrlich, had devised the world’s first effective treatment for syphilis by attaching toxic arsenic to a Treponema pallidum binding dye: missile and warhead.
But one hundred years later scientists were able to come up with a better missile than an aniline dye. The obvious modern missile was going to be some type of highly selective monoclonal antibody. The problem was that the monoclonal antibody carrier had to be designed so as not release any toxic calicheamicin until it reached the cancer cell. Then, upon reaching the cancer cell, it had to dump its entire toxic payload. Not easy. It took ten years of hard work to get there, resulting in the development of gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth) . The gemtuzumab ozogamicin antibody binds CD33, a myeloid-specific cell surface protein that targets the calicheamicin for the treatment of acute myeloid leukemia (AML). But frustrating everyone involved, gemtuzumab ozogamicin did not turn out to be the magic bullet. Ten years post launch gemtuzumab ozogamicin was removed from the market in the United States at the request of the U.S. Food and Drug Administration (FDA). After years of clinical experience the FDA concluded that the drug was still too toxic, although it is still being used in Japan and studies continue to support the re-approval of this agent .
Needed: A Tremendous Dose of Luck
Among the members of the calicheamicin team, George Ellestad was a very special kind of person. George’s hobby was trekking in the Himalayas in Nepal. (No, none of the soil samples he brought back from Nepal ever produced a drug). He was a natural scientific leader, but avoided any and all formal scientific management roles. He was a pure bench scientist. When George spoke up at meetings he was so authoritative that everyone would immediately focus and listen carefully to him, listen much more carefully than they would listen to the big management bosses who also spoke at these meetings. People would mistakenly characterize George as a high level manager. “No”, he would insist, “I’m just high bench”. George is one of these unsung heroes of industrial science – someone who was effective way beyond his rank but not adequately formally recognized.
His colleague, Nada Zein was a passionate scientist whose lifelong goal was to pursue and discover the truth. She never let her career goals get in the way of that pursuit, exemplifying a quote from the famous 20th century philosopher, Ludwig Wittgestein: “Ambition is the death of thought.” Nada was passionately thoughtful. I got to know Nada in no small part because she married a terrific chemist collaborator of mine named Doug Phillipson, with whom I had worked with in a previous job. If it seems like all drug hunters know one another, that’s because it’s true. We’re an amazingly small community.
Doug and I worked on a number of drug projects together, with me leading the biology and Doug leading the chemistry. We were also good friends outside the lab. Doug sold me his favorite car, a little white 1993 Mazda Miata, which he had meticulously kept in near brand new condition but could not financially justify taking with him when he moved from New Jersey to California in the late 1990’s. Over 20 years later the car is still running just fine. Doug was totally trustworthy both as a scientific collaborator and a used car salesman.
One project that Doug and I worked on together was the development of a novel antifungal drug. At the time the AIDS crisis was in full swing and, prior to the development of effective antiviral drugs, fungal infections were producing 70% of the morbidity in AIDS patients. Squibb** management felt that only one therapeutic approach was justified: to target the enzyme that was hit by the azole antifungals, drugs like miconazole (sold a Micatin Cream for vaginitis) that were first discovered in the late 1960’s. And after years of toil by a large group of Squibb scientists we finally found what management had asked for: lanomycin, a structurally novel antibiotic acting on the azole target. However, just as the discovery was made management abruptly reversed themselves and withdrew all support from our lanomycin lead. The Greek gods should have sentenced Sisyphus to a lifetime of drug hunting. Doug tried to keep the project going under the radar without management approval, but alas, with only minuscule resources lanomycin was never going to be turned into an FDA approved drug. (Ultimately the pneumocandin antifungals, compounds with a novel anti-cell wall mechanism of action, turned out to be the answer.)
Nada pursued a number of scientific initiatives after her work on calicheamicin, moving from Lederle to the Genomics Institute of the Novartis Research Foundation in La Jolla, California. At the Novartis Foundation in La Jolla she was seeking to mate drug ligands to receptors, but soon came to the conclusion that this goal would be elusive due to management and leadership issues in the pharmaceutical industry. So she decided instead to study for a master’s degree in social work and for years ever since has been working as a marriage counselor. Counter-intuitively it appears that it was easier for her to bind spouses together than drug ligands and their targets. Go know.
The discovery of new medicines is brought forward by the dreams, aspirations and creative spirit of all those involved. But despite all the great ideas and hard work you still need a tremendous dose of luck.
* Lederle Laboratories was purchased from American Cyanamid in 1994 by American Home Products Corp., and the Pearl River operation was renamed Wyeth-Ayerst. American Home Products renamed itself Wyeth in 2002 and became a piece of Pfizer in 2009. Today, the Pearl River campus is one of Pfizer’s five primary research sites and a central hub for Vaccine and BioTherapeutics research. The company also manufactures a number of oncology drugs at the Pearl River, including Mylotarg®.
** Squibb Corporation was founded in 1858 by Edward Robinson Squibb in Brooklyn, New York, New York. E.R Squibb was known as a vigorous advocate of quality control and high purity standards within the fledgling pharmaceutical industry of his time, at one point self-publishing an alternative to the U.S. Pharmacopeia (Squibb’s Ephemeris of Materia Medica) after he was unable to convince the American Medical Association to incorporate higher purity standards. References to the Materia Medica, Squibb products, and Edward Squibb’s own opinion on the utility and best method of preparation for various drugs are found in many medical papers and journals of the late 1800s.Squibb Corporation served as a major supplier of medical goods to the Union Army during the American Civil War, providing portable medical kits containing morphine, surgical anesthetics, and quinine for the treatment of malaria (which was endemic in most of the eastern United States at that time). Squibb merged in 1989 with Bristol-Myers (founded in 1887 by Hamilton College graduates William McLaren Bristol and John Ripley Myers) to form Bristol-Myers Squibb.
January 17, 2017 | Corresponding Author: Donald R. Kirsch | DOI: 10.14229/jadc.2017.17.01.001
During the (early) preclinical drug development process as well as manufacturing of biopharmaceutical (protein) products, analysis and characterization are crucial in gaining a better understanding of the physical and chemical properties of various materials. These properties can have an impact on the manufacturability as well as the performance, potential for metabolism, stability and appearance of a specific medicinal product. Hence, properly characterizing these products is essential for a drug candidate to move from drug development to regulatory approval and, finally, the clinic.
In recent years, complex biopharmaceutical drugs and biologics have evolved into mainstream therapeutics. The manufacturing of these compounds, including monoclonal antibodies, bispecifics, antibody-drug conjugates (ADCs), recombinant and other therapeutic proteins, require extensive analytical and comprehensive characterization using a variety of techniques, including non-compendial, and sometimes an intricate quality control methodology, to confirm manufacturing consistency and product quality.
Because biopharmaceuticals and biologics exhibit highly diverse structures and broad biological activities, a study of these agents is a relatively complex process requiring sophisticated analytical techniques. Furthermore, in addition to these complexities, regulatory expectations to better understand product impurities and degradants in biopharmaceutical products continue to increase.
As a result, many drug developers may find that their current global chemistry, manufacturing, and control (CMC) systems are quickly becoming obsolete. Consequently, new, highly sensitive and specific technologies are becoming the new normal.
Keywords: Biopharmaceutical analysis, Characterization, Protein therapeutics, Bioanalytical methods, Structure and function, Physical and Chemical properties
2.0 New Analytical Approaches
The field of monoclonal antibodies, launched with Köhler and Milstein’s initial study published in 1975 of a method to produce fully intact murine IgG antibodies, has created a new area of the development of novel medicinal products.  In the more than three decades since the initial development of monoclonal antibodies, chimerization, humanization and fully human antibody technology followed. 
Subsequent to the growth of antibody-based products, new technologies have emerged for creating modified forms of antibodies, including antibody fragments, antibody-drug conjugates or ADCs as well as bi- and multi-specific antibodies.
In the development of these next-generation medicinal compounds, a better understanding of currently approved ADCs and novel site-specific bio-conjugation technologies is required. For example, a better analytical understanding of the structure-activity relationship accelerates the discovery and development of the next-generation ADCs with defined and homogeneous compositions.
Analytical methods and characterization for novel biopharmaceuticals and biologics involve complex, multi-faceted procedures stretching from early (pre-) clinical drug discovery to clinical development, regulatory approval and, finally, market entry.
Most of this work takes place during the early development phase, and is vital to help understand the influence of process changes, measured against an established reference standard.
3.0 Protein Therapeutics
Biopharmaceutical therapeutics are inherently challenging to characterize because of their complexity and natural heterogeneity. Therefore, appropriate and complete analysis ensures meaningful and reliable characterization, and provides the data required to satisfy regulatory requirements concerning product identity, (im)purity, concentration, potency, stability, safety and overall quality.
Methods used to characterize primary and higher-order structures (including techniques to determine protein sequence, posttranslational modifications, folding and aggregation) and protein concentration (including amino acid analysis, intrinsic protein absorbance and colorimetric methods) are vital to avoid aberrant results for key attributes that could, potentially, raise quality issues.
In addition, characterization and analysis of biopharmaceutical proteins also involves product- and process-related determination of impurities, which may compromise the safety of the protein therapeutics. This includes various assays (including bioassays and noncell-based binding assays) for determining the functional activity of proteins, which may be indicative of potency.
Overall, a complete approach to characterization helps developers to be confident that their product meets regulatory requirements as well as product quality and safety standards.
4.0 Changing Technologies
While spectrophotometric analyses of proteins are commonly used, there may be a number of important reasons to change analytical methods and characterization techniques.[a]
The reasons may include:
New techniques may allow for better characterization, making it possible to follow the stability of specific molecules and proteins, as well as contribute to deeper understanding of them. New techniques may include imaging, capillary-electrophoresis, ultra-high-resolution mass spectrometry, micro-flow imaging (MFI), etc.; (Figure 1.0)
Improved technologies to replace legacy methods. Examples include using ultra-high-performance liquid chromatography (UHPLC), a relatively new technique giving new possibilities in liquid chromatography, instead of high-performance liquid chromatography (HPLC) and Capillary Western (WES), a quantitative western blot produced by a protein simple, which offers increased precision and specificity versus ELISA; (Table 1.0)
Formulation and process changes may occur in the early stages of drug development. Even through Clinical Trial phase I and phase II, there may be formulation or process changes, which may require additional or new analytical methods;
There may an interfering compound within the formulation. One example is the use of surfactants[b], such as Polysorbate 80[c](also known as PS80) which may interfere with the reverse-phase method. To be certain about stability, when observing new degradants, it may be required to use a new method that will resolve and quantify the new analytes;
There are specific regulatory requirements that apply to approved products, including the expectation of periodic method assessment for improvement;
Many techniques allow for strategic business decisions, resulting in high throughput with low costs. This largely depends on how many lots and stability studies are necessary. In turn, this may directly impact the costs associated with the regulatory approval process of products being developed.
5.0 Regulatory Implications
The regulatory process established by the U.S. Food and Drug Administration (FDA) requires that each New Drug Applications (NDA) and Abbreviated New Drug Application (ANDA) includes the analytical procedures necessary to ensure the identity, strength, quality, purity and potency of the drug substance and drug product.  Furthermore, each Therapeutic Biologic Application (BLA) needs to include a full description of the manufacturing process. This includes analytical procedures that demonstrate that the manufactured product meets prescribed standards of identity, quality, safety, purity and potency. 
The analytical procedures and methods validation for drugs and biologics, Guidance for Industry, states that, over the life cycle of a medicinal product, new information (e.g., a better understanding of product characteristics) may warrant the development and validation of a new or alternative analytical method. 
But analytical methods should not be considered to be “locked down” or validated once clinical trial phase I or phase II is reached. To fully understand the biopharmaceutical products involved, the FDA requires scientists to consider new or alternative analytical technologies, even after completion of the drug approval process.
The FDA also requires that drug developers and manufacturers periodically evaluate the appropriateness of an analytical method and consider new or alternative methods. To make this process simpler and more robust, and in anticipation of life cycle changes in the analytical process, an appropriate number of drug samples should be archived to allow for comparative studies. These samples must not only be put away for stability studies, but a reasonable number of samples should be archived at the proper temperature (typically at -80 degrees for a biopharmaceutical sample) to be used for crossover and comparability studies. This is critical to smoothing the pathway for change from one analytical method to another. 
6.0 Regulatory Reporting Requirements
Establishing a regulatory framework, the FDA sets “safety reporting requirements for human drugs and biological products” that include mandatory reporting of any change in analytical methodology, and describes—among other things—a developer’s responsibilities for reviewing information relevant to the safety of an investigational drug and their responsibilities for notifying FDA. These reporting guidelines cover minor, medium and major changes. (See: Table 2.0)
6.1 Minor Changes
Minor changes are those within the “validated change of the analytical method.” For example, when a validated chromatography method for a column temperature range of 10° to 40° change from a nominal of 30° to 35°, this would be considered to be a minor change. While this change can be submitted as part of the annual report, it is still required that the applicant reports the change to the agency. 
The Guideline for Industry detailing the requirements for the annual report stipulates that properly reporting post-approval manufacturing changes must be made in compliance with current Good Manufacturing Practice (cGMP). 
6.2 Moderate Changes
At the moderate level, the validated range is exceeded in certain parameters. Such a change may have an adverse effect on the identity, strength, quality, purity or potency of the drug product. Using chromatography as an example, this could be a change in mobile phase from acetonitrile to methanol, or a change in the actual gradient of a method. Such a change has more stringent requirements and required validation of this new method in additional comparability studies.
6.3 Major Changes
Major changes include modifications that establish a new analytical method, eliminate a current method (substituting one method for another rather than adding a new method), or delete or change the acceptance criteria for a stability protocol.
At the major level, there are substantial changes to the analytical method. For example, a major change includes switching from UV detection to mass spec (MS-) detection. Such a change must be validated with a formal, highly statistical comparability study designed to show any differences, or lack thereof.
In case of a major change, developers are also required to submit and receive FDA approval of a supplemental application to the original NDA or ANDA. In what is known as a Prior Approval Supplement (PAS), a major change needs to be reported and include a detailed description of the proposed change, which products were involved, a description of the new method, the validation protocols and data, a description of the changes to evaluate the effect of the change, a comparability report, a description of the statistical method of evaluation and a final study report. 
While a PAS is generally required for approved drugs, it also sets expectations for early-phase products. Although they are not covered under formal CFR regulations, the FDA does, in fact, expect at least a similar study to be performed when a drug is in clinical trial phase I, II or III.
7.0 Comparability Study
The comparability process is critical. The FDA requires that a manufacturer carefully assess manufacturing changes and evaluate the product resulting from these changes for comparability to the pre-existing product. In such a case, the goal is to show that a new analytical method is superior to the original method. 
Based on the guideline for industry, determinations of product comparability may be based on chemical, physical and biological assays and, in some cases, other nonclinical data. This requires referring to archived samples from historical batches, and whether those are included in the Investigational New Drug (IND) submission, clinical or registration batches. 
This is a critical part of the process, because developers need to show that a new method is more sensitive or selective, and is therefore detecting and quantifying impurities or degradants that were always present, but not seen by the current (existing) method and, as a result of a change of methodology, can now be better monitored.
8.0 Comparability Design
A well-planned comparability design will assess the effect of CMC changes, allowing the FDA to determine if a specified change can be reported in a category lower than the category for the same change. Appropriate samples should be included, allowing a comparison of the ability of the new and original method to detect relevant product variants and degradation. This approach provides sufficient information for the FDA to determine whether the potential for an adverse effect on the product can be adequately evaluated.  
To be adequate, the number of batches should be statistically relevant. The guidance to industry emphasizes the use of a trained statistician. The reason is that, while the FDA recognizes that a comparability design is less complicated than a clinical trial, it requires a statistician to design a robust program clearly showing differences between methods. 
There are a number of concerns associated with the development and the implementation of new methods designed to replace a current (existing) method. The biggest question is whether the results of the analytical methods will be different.
In general, the expectation is that by changing analytical methods, there is indeed a fairly high probability of getting different results. Hence, if there is a change to an improved method, the ideal scenario is a change in sensitivity or specificity, which would therefore show an additional or higher level of impurities or degradants.
Another concern is assay bias. For the statistical analysis of data, it is important that both the new and old data are within specification. Based on the guidelines to industry, the cause of bias must be examined to see if such bias has an effect on the data. Hence, analyzing archived samples to show that impurities and degradants were always present is crucial.
For products that have already been marketed, there is a concern that new impurities may result in the requirement for new, additional, clinical work. If there are archived samples to show that the materials were always there, the clinical data will still prove that the drug is safe and efficacious, and that the newly measured impurities and degradants could not be measured with the previous method.
If such is the case, statistical analysis is still necessary to justify the bias; however, there is no need for additional clinical work. The new process is just implemented to compare and show an improved method. 
Preclinical drug discovery and development process, as well as manufacturing of biopharmaceutical products, involves a complicated process including rigorous (experimental) scientific study. By following regulatory guidelines, successful advancement of novel drug candidates requires early planning, setting aside archived samples, having a very tight validation report and study and, finally, having a well-planned, statistically rigorous comparability study.
If these steps are present, there is a high probability of a smooth regulatory process. Drug developers may expect to receive approval to use the new analytical method for a marketed product. And if the product is in a preapproval process, the expectation is that there is no need for additional questions from the agency.
Footnotes [a]UV-VIS spectroscopy (ultraviolet and visible spectroscopy) is typically used for the determination of protein concentration by either a dye-binding assay or by determining the absorption of a solution of a protein at one or more wavelengths in the near UV region (260-280 nm). Circular dichroism is another spectroscopic method used in the early-phase characterization of biopharmaceuticals (proteins). [b]Surfactants are compounds that lower the surface or interfacial tension between two liquids. [c]Polyoxyethylene-sorbitan-20-monooleate [d] UHPLC and UPLC (Waters Corp.) allow for better separation of peptide mapping [e]CBE-30 is similar to Changes Being Effected (CBE) and involves a filing with the FDA to gain approval of a moderate change (this may include a change that has a moderate potential to have an adverse effect on the identity, strength, quality, purity or potency of the drug product, as these factors may relate to the safety or effectiveness of the drug product. Based on the CBE-30, the FDA has 30 days to respond prior to implementation of any change. If a filer does not receive a reply from the FDA within 30 days, it is assumed that a change is approved. [f]Chemistry, Manufacturing and Controls (CMC) is renamed to Pharmaceutical Quality/CMC
Over the last decade, Targeted Therapies, Personalized and Precision Medicine have become part of our vocabulary, representing a new way of thinking in how we address cancer and hematological malignancies. The conventional one-disease-one-treatment-model is gradually being replaced by individualized care that is catered towards a patient’s unique needs. However, to be successful, these new approaches depend on the availability of accurate and reliable diagnostic tests to help determine which therapeutic product will be most appropriate and effective for an individual.
The U.S. Food and Drug Administration (FDA) plays a critical role in advancing personalized and precision medicine. Currently, the FDA is at work on a regulatory platform that is set to ensure accuracy while promoting innovation.
The optimization of the FDA’s regulatory oversight on personalized medicine was one of the popular topic being discussed at this year’s American Association of Cancer Research’s Annual Meeting in New Orleans, LA (April 16 – 20, 2016). Several presentations reviewed current efforts to improve the co-development of treatment and companion diagnostic tests by advancing the regulatory process and updating current standards, as well as initiatives in improving the way Next Generation Sequencing data is validated and accessed. 
Companion and Complementary Diagnostics
In the session FDA Regulation of Companion and Complementary Diagnostics (Saturday, April 16, 2016, 11:00 AM -12:00 PM) Pamela L. Bradley and David Litwack, both from the U.S. Food and Drug Administration, Silver Spring, MD, discussed general principles that can advance co-development programs and share lessons learned from the numerous successful co-development programs in oncology. The presentation emphasized how the role of FDA regulation becomes especially important when a companion diagnostic is required for the safe and effective use of a specific therapeutic product. In various cases certain FDA regulatory requirements apply, including contemporaneous marketing authorizations. This means that development programs for a novel therapeutic, as well as the diagnostic test, need to be co-developed in a process that ensures the reliability and safety of both companion test and treatment.
Bradley and Litwack also discussed so-called complementary diagnostics. While similar, complementary diagnostics, which can provide important information for individual benefit-risk decisions related to treatment with a particular therapeutic product, are not the same as companion diagnostics. The presentation clarified that while a complementary diagnostic is able to provide additional information as to how a drug might be used, it is not the same as a companion diagnostic, which is essential for the safe and effective use of a drug. Since complementary diagnostics add another factor to the regulatory process, there is even greater need to advance and modernize FDA approval processes and standards- a topic that was further developed by the FDA’s Katherine Donavan and Laura Koontz (U.S. Food and Drug Administration, Silver Spring, MD) in an educational session later that Saturday. 
New FDA Initiatives
In the educational session New FDA Initiatives in Personalized Medicine (Saturday, April 16, 2016, 3:00 PM -4:30 PM), Donavan and Koontz provided a broad overview of current cross-agency initiatives as well as agency efforts to enable the regulatory flexibility needed to accelerate diagnosis and treatment in oncology. Topics included the Precision Medicine Initiative, laboratory developed tests, next generation sequencing, and the development of accurate and relevant clinical databases.
During the first portion of the presentation, Donovan described some of the lessons learned from past companion diagnostic approvals, as well as how the FDA is currently defining both companion and complimentary diagnostics. The importance of co-approval when it comes to companion drug diagnostic combinations was also emphasized. In fact, the FDA is actively looking to evolve the current co development model in several ways. One of these has been the creating of a co-development “How-to” manual, which will provide important consideration points for both therapeutic and diagnostic development programs, with the goal of supporting contemporaneous market authorization. This draft guidance is currently being developed and reviewed internally, and will include advice on how to plan ahead for test validation, guidance on co-development and clinical trial designs, as well as important points for planning ahead for FDA review and contemporaneous approval. 
Afterwards, Laura Koontz gave a broad overview of the Precision Medicine Initiative (PMI): a research effort launched by President Obama in 2015 that aims to enable and empower the researchers, clinicians, and patients, by advancing the research, technology, and policies relating to individualized care.
There are several factors that will enable the success of PM. Above all, safe and accurate diagnostic tests are essential, as they can reliably identify an individual variation and select treatments accordingly. 
Next Generation Sequencing (NGS)
At the forefront of these tests is the use of Next Generation Sequencing (NGS), which can identify thousands — even millions — of genetic variants in order to use these results to diagnose or predict an individual’s risk of developing many different conditions or diseases. Since each individual’s DNA varies slightly, NGS is powerful tool allowing scientists to look for meaningful DNA differences that can suggest a person’s risk to disease, current health state, and very importantly, predict response to particular treatments.
Currently, NGS technologies are rapidly entering clinical practice, but there are a number of regulatory issues and challenges that these types of tests face. In response to these challenges, the FDA is working toward the goal of developing and implementing an adaptive standards-based regulatory approval which works toward ensuring quality and relevance of data from NGS tests. Recently, the PrecisonFDA web platform was launched in efforts to reach this goal. Precision FDA is an online portal which allows researchers and industry and government professionals to come together and promote innovation while developing a science behind interpreting NGS.
Another important factor for the advancement of NGS tests is making sure that researchers and clinicians can access reliable and quality genomic data. In order to do so, the healthcare system must be leveraged so that data gathered from genomics can be systematically kept and organized. Curative data bases are essential in providing important clinical evidence, and according to Koontz, the FDA is looking into whether or not a regulatory grade database could be used as a source of information to support the link between a specific genetic variant and disease.
“To really implement this, we need to address issues of data quality,” Koontz emphasized. “The FDA wants to be able to say that use of these meets our requirements for clinical validity, and ensure that the data is high quality, and that any assertion made is as accurate as possible and based on current knowledge,” he continued
Koontz further noted the importance of the development of new targeted therapies, a topic widely discussed throughout the conference, and how research and regulatory policies need to catalyze the advancement of these treatments, while protecting patients at the same time. And while targeted therapies and personalizing treatment adds layers of complexity and regulatory challenges, the FDA is focused on modernizing to meet the needs of a new era in precision medicine.
“We are working diligently to propose standards with the input of the scientific community,” noted Koontz. “We are really looking at standards that can be updated as the science and technology advance,” he concluded.
Forty- five years ago, in a room filled with congressional members from both sides of the isle, distinguished guests, and a contingent of press, President Richard M. Nixon signed the National Cancer Act, officially launching what has become known as the “war against cancer”.
In his remarks that day, the president predicted that history would look back on the occasion as being the most significant act of the Nixon presidency. With the exception of establishing diplomatic relations with the Peoples Republic of China, and the activities a small group of bungling cat burglars who attempted to break into the offices of the Democratic National Committee (DNC) at The Watergate hotel, it turns out that President Nixon was an accurate prognosticator. The National Cancer Act established an infrastructure that has been used to fund and conduct over $100 billion of cancer research, and is responsible for much of the basic knowledge about cancer that we have gained, and the progress we have made in the fight against cancers.
Video 1.0: President Nixon signing the National Cancer Act of 1971 on December 23, 1971. Nixon addresses the the importance of cancer research, signs the the bill, and listens to remarks by the president of the American Cancer Society (ACS).
The question is, in the political climate of today, would legislation as significant as the National Cancer Act ever become a reality, and will our next president have the desire and opportunity to implement the reforms necessary to accelerate our progress, and position us to finally win the war against cancers?
Hot button issues
Let’s take a quick look and a handful of the “hot button” issues that predominate the current political scene, and how they compare to or are impacted by cancers:
Gun Control: It is estimated that approximately 30,000 people in the U.S. will be killed by gun violence this year. In comparison, 600,000 people will die from cancer related illnesses.
Same sex marriage: Overall, 3.9% of Americans identify as LGBT. According to the American Cancer Society, 39.6% of Americans will get some type of cancer over their lifetimes.
Affordable Care Act: In 2016, subsidies of insurance premiums under the Affordable Care Act will cost the government approximately $300 billion. In 2011, the most recent year for which statistics are available, the costs of cancer care in the U.S. were approximately $125 billion, the most of any category of diseases.
Wall Street: Mortgage backed securities and the implosion of the U.S. housing market in 2007 led to the worst financial crisis since the great depression. The ongoing cancer pandemic has the potential to overwhelm public health systems, bankrupt private health insurers, and impoverish patients, resulting in economic devastation that is multiple times the magnitude of the 2007 housing crisis.
Economy: When including the costs for treating cancers, the annual total global cost of cancers in 2010 was estimated to be $2.5 trillion, which represents approximately 4% of the world GDP.
Clearly, the importance of the ongoing national cancer healthcare crisis far exceeds many of the issues that we hear the candidates talk about on a daily basis. Is it possible to get the candidates focused on cancer, and if so, how do we get them, and in turn our next president, to make the ongoing cancer epidemic a priority?
Cancer is complicated
Cancer is complicated. It is comprised of over 150 different diseases, and each disease has multiple subtypes. Cancer cannot be addressed in a single sound byte, and any talk of finding a “cure” for cancers is rubbish, and nothing more than political rhetoric. The good news is that we are on the verge of some significant breakthroughs in how we approach cancers, and with advances in early cancer detection technologies, and immunotherapies, we have the opportunity to significantly reduce cancer mortality rates in the U.S. within the next 5 to 10 years. To use a football analogy, we are in the “red zone” when it comes to cancers.
Focusing on the ongoing cancer crisis
The way for us to make cancers a priority for the next administration is to work backwards. For the president to come into office with a comprehensive plan to address cancers and accelerate our progress in the fight against cancers, we need to get the presidential candidates focused on the ongoing cancer crisis. To get the candidates focused on the ongoing crisis, we need to show the candidates that cancer is important to voters, and that in a close election, a candidate’s platform for addressing the cancer crisis could swing the election. That is the impetus behind Cancer4Pres.org.
Apolitical campaign Cancer4Pres.org is an apolitical website and campaign, with the ultimate objective of making the ongoing cancer crisis a priority for our next presidential administration. Visitors to the Cancer4Pres.org website can click the “Cancer Counts” button to show the candidates that cancer is important to voters, and visitors can send personalized emails to the candidates in honor of people that they know that have been affected by cancer. The candidate’s have been invited to use the Cancer4Pres.org forum to present their platforms for addressing the cancer crisis.
Some have called for the appointment of a National Cancer Czar, much like we have had for AIDS, for the purpose of coordinating all of the government cancer related research and activities (by the way, approximately 1.6 million people worldwide are expected to die from AIDS related illnesses this year, compared to8 million worldwide deaths from cancer related illnesses).
Other ideas, such as the sharing of cancer data among companies, “fast tracking” new cancer treatments, updating our cancer diagnostic technologies which have become outdated and in some cases obsolete, changing the rules with govern cancer drug trials to give clinicians the flexibility that they need to design drug trials that address the ever changing morphologies of certain cancers, are just a sampling of the many prospects for cancer reform that are being discussed by experts.
There is no shortage of possibilities that could improve the current cancer landscape and it is up to each candidate to analyze the flaws and inefficiencies in our current approaches, and to exercise the judgment necessary to pick and choose the right combination of changes and improvements to form the basis of that candidate’s cancer platform. Once that occurs, it would be up to the voters to decide which candidate has the cancer platform that would be most effective, and which candidate has the leadership skills to take us from the red zone, into end zone.
Bipartisan support – an illusion?
Whether our incoming president can generate the bipartisan support that might be necessary to enact new cancer legislation and new cancer policies remains to be seen. In today’s political environment, members of the same political party are reluctant to agree to be in the same room together, and the type bipartisan cooperation that we saw 45 years ago when President Nixon signed the National Cancer Act, seems like a thing of the past. But if there is one issue that has the potential to not only unify a political party, but perhaps the entire nation, it is cancer.
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Robert Berman is the co-founder of Cancer4Pres.org. He is also the President and CEO of ITUS Corporation, whose subsidiary company, Anixa Diagnostics Corporation, is developing a blood test for the early detection of cancers.
Marketing of prescription medications and medical devices directly to consumers has, for many years, been the focus of considerable – ongoing – debate.
Proponents argue that Direct-to-Consumer or DTC advertising of prescription drugs is an important tool to informs and educate consumers – as well as patients – about important, treatable health conditions. It encourages and stimulates, they say, doctor-patient communication. Critics, on the other hand, say that this type of advertising is one of the main causes contributing to rising drug costs. It also leads, according to the critics, to people demanding unnecessary or inappropriate medical treatments – leading to a general increase in healthcare – and health insurance costs.
In the United States, prescription drug advertising was, traditionally, directed primarily toward healthcare professionals and not to consumers and patients. However, as early as the 1980s, DTC advertising of prescription drugs began to appear in print media and, over time, increasingly spread to radio and television formats after the publication of the FDA guidance for industry, Consumer-Directed Broadcast Advertisements, which was published in 1997.  With the increase of DTC advertising, critics started to worry about the potential of problems for consumers and the healthcare system
Patient care can be compromised and delayed when prescription drugs are unaffordable …. in a worst-case scenario, patients forego necessary treatments when drugs are too expensive
Results of a Food and Drug Administration survey published in 2002 suggest that most physicians view DTC as one of many factors that affect their medical practices and their interactions with patients. Furthermore, physicians confirm that DTC advertising of prescription drugs on radio and television and in magazines, has, in general, positive and negative effects on their patients and practices.
What patients think
The same 2002 survey showed that about three out of four patients agreed that DTC advertisements increased their awareness of a new drugs. Another 58% of the interviewed patients felt that the ads also provide enough information to make a decision about whether to discuss the drug with their physician. In terms of specific content, roughly 60% of patients felt DTC advertising did not provide enough information about risks while 44% believed the ads lack adequate benefit. 
One of the arguments used by proponents of DTC advertising is that they believe that it promotes doctor-patient communication. The FDA survey confirmed that 73% of patients agreed that DTC advertisement did not minimize the role of the physician in final product decisions while 43% felt that it helped them have better discussions with their doctor. The survey also showed that 10% of patients were reluctant to talk to their doctors about an advertised drug for fear of implying a distrust of the doctor.
Overstatement, accuracy and benefit
The 2002 FDA survey showed that with regard to claims that pharmaceutical companies make, a little more than half (58%) believed the ads make products seem better than they really are while 42% felt the advertisements make it seem like the drug will work for everyone. However, 32% of the patients felt that DTC advertising helped them make better health decisions.
One of the unexpected benefits observed by the investigators was that 18% of responding patients confirmed that DTC advertisements improved drug adherence since it reminded them to take their medications.
Studying the impact of prescription sales
More than a decade ago, the Kaiser Family Foundation commissioned a study designed to find out how DTC impacted prescription drug sales. Conducted by researchers at the Harvard School of Public Health, Massachusetts Institute of Technology, and Harvard Medical School, this study examined changes in direct-to-consumer (DTC) advertising and physician promotion activities between 1996 and 1999. One of the questions the researchers wanted to answer was how DTC advertising effected drug sales within five specific therapeutic drug classes as well as variations in advertising patterns and product life-cycles of drugs within these classes.
After accounting for the fact that drugs with higher sales are more likely to be advertised to consumers and have higher levels of promotion to physicians, the study found that increases in DTC advertising was associated with significant growth in sales for the classes of drugs studied. They found that, on average, for every 10% increase of DTC advertising, drug sales within that classes increased by 1% (in real dollars, every $1 the pharmaceutical industry spent on DTC advertising in that year yielded an additional $4.20 in drug sales). Interestingly, the researchers did not find evidence that changes in DTC advertising affected the market share of individual drugs within each of the selected classes, they confirmed that DTC advertising was responsible for 12% of the increase in prescription drugs sales, or an additional $2.6 billion, in 2000.
In their report, published in 2003, The Kaiser Family Foundation concluded that although DTC advertising was indeed an important driver in the growth of prescription drugs spending, it was not the primary cause. The researchers also concluded that the return generated by increasing spending on DTC advertising appeared to be significant for the pharmaceutical industry and that given this continuing rapid growth, the debate over the costs and benefits of DTC advertising was likely to continue. 
A new policy
Now, almost 13 years later and responding to the billions of advertising dollars being spent to promote prescription products, physicians at the Interim Meeting of the American Medical Association (AMA), the premier national organization dedicated to empowering the American physicians to continually provide safer, higher quality, and more efficient care to patients and communities, adopted a new policy aimed at driving solutions to make prescription drugs more affordable.
Physicians cited concerns that a growing proliferation of DTC advertisement is driving demand for expensive treatments despite the clinical effectiveness of less costly alternatives.
“Today’s vote in support of an advertising ban reflects concerns among physicians about the negative impact of commercially-driven promotions, and the role that marketing costs play in fueling escalating drug prices,” said AMA Board Chair-elect Patrice A. Harris, M.D., M.A. “Direct-to-consumer advertising also inflates demand for new and more expensive drugs, even when these drugs may not be appropriate.”
The United States and New Zealand are the only two countries in the world that allow direct-to-consumer advertising of prescription drugs. Advertising dollars spent by drug makers have increased by 30% in the last two years to $4.5 billion, according to the market research firm Kantar Media.
The newly adopted AMA policy also calls for convening a physician task force and launching an advocacy campaign to promote prescription drug affordability by demanding choice and competition in the pharmaceutical industry, and greater transparency in prescription drug prices and costs.
“Physicians strive to provide the best possible care to their patients, but increases in drug prices can impact the ability of physicians to offer their patients the best drug treatments,” Harris noted. “Patient care can be compromised and delayed when prescription drugs are unaffordable and subject to coverage limitations by the patient’s health plan. In a worst-case scenario, patients forego necessary treatments when drugs are too expensive.”
According to Harris, the new AMA policy responds to deepened concerns that anticompetitive behavior in a consolidated pharmaceutical marketplace has the potential to increase drug prices. Harris said that the AMA will encourage actions by federal regulators to limit anticompetitive behavior by pharmaceutical companies attempting to reduce competition from generic manufacturers through manipulation of patent protections and abuse of regulatory exclusivity incentives.
In addition to the more influence of regulators, Harris said that the AMA will also monitor pharmaceutical company mergers and acquisitions, as well as the impact of such actions on drug prices. Patent reform is a key area for encouraging greater market-based competition and new AMA policy is expected to support an appropriate balance between incentives for innovation on the one hand and efforts to reduce regulatory and statutory barriers to competition as part of the patent system.
Last month, the Kaiser Family Foundation released a report saying that a high cost of prescription drugs remains the public’s top health care priority.
The new Kaiser Family Foundation survey confirms the impact of DTC advertising on prescription drug pricing but suggests the impact of these drug ads may be both good and bad, something also mentioned in the Food and Drug Administration survey published in 2002.
According to the new report, a significant number of people go to their doctors and ask for a specific drug because they’ve seen an ad. However, the Kaiser Family Foundation researchers fund that only some patents will indeed get the requested drugs after their physicians sort through treatment options with them. Unfortunately based on this survey the researchers couldn’t say how often this is a good thing or a bad thing medically. However, they, could say that almost certainly, more drugs are prescribed as a result of DTC advertisements .
The AMA’s new policy recognizes that the promotion of transparency in prescription drug pricing and costs will help patients, physicians and other stakeholders understand how drug manufacturers set prices. If there is greater understanding of the factors that contribute to prescription drug pricing, including the research, development, manufacturing, marketing and advertising costs borne by pharmaceutical companies, then the marketplace can react appropriately.
Although the AMA calls for a ban, given the impact of such as ban, the debate over the costs and benefits of DTC advertising is likely to continue.
Last Editorial Review: November 17, 2015
Feature Image: Prescription Drugs / Pills . Feature image Courtesy: Pixabay/Frauke Feind 2015. This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. CC BY-SA 3.0