A clinical trial is a culmination of the several stages of a drug or medical device development program that begins with the discovery of a candidate molecule followed by preclinical toxicology studies in ex vivo, in vitro, and animal models. Once the candidate molecule shows promising results in these stages, the next step involves clinical studies on human subjects. Drug testing in humans is often the most lengthy and expensive phase of the drug development timeline, and therefore requires extensive effort and careful execution to maximize the candidate’s chances of success. In addition to scientific evaluation, clinical studies require approval by the United States Food and Drug Administration (US FDA), the regulatory authority in the United States to administer the experimental drug in humans as well as ship it across state lines. This approval comes in the form of an Investigational New Drug (IND FDA) application that is required to be submitted by sponsors, investigators, or research institutes to the FDA to commence studies on human participants. The following figure shows the various stages of the drug development program (Figure 1) marking IND submission on the timeline.

The US FDA submission process is a critical step to ensure the safety and efficacy of new drugs. To ensure compliance with the FDA, drug developers must have an effective data strategy in place. This includes understanding the IND data requirements and having the plan to collect, analyze, and submit all relevant information to the FDA. With a well-thought-out drug development strategy in USA,  drug developers can maximize their chances of success when submitting their new drugs for review.

Figure 1. Schematic representation of drug development stages

Why is an IND required?

The IND is a comprehensive document that contains all the information gained from preclinical and other studies in an organized format. The FDA reviews and makes the decision to support further clinical studies from information in the IND that ultimately forms the basis of marketing approval. INDs can be submitted at any phase during clinical development to protect the safety and rights of subjects (Phase I) and to assure adequate scientific evaluation of the drug’s effectiveness and safety (Phase II and III). The Code of Federal Regulations CFR Title 21. Part 312 Investigational New Drug Application contains information on INDs as well as their content and format and should be reviewed thoroughly by sponsors or investigators prior to submission of an IND application.

An Investigational New Drug (IND) application is an essential part of the process for conducting a Phase 1 clinical trial in the United States. The IND is required by the FDA before any investigational drug can be tested on humans. It ensures that the drug has been properly tested, manufactured, and labeled for safety and efficacy before it can be used in a clinical trial. The IND also contains detailed information about the proposed study design, investigator qualifications, and other necessary information to ensure that the trial will be conducted safely and ethically. By having an IND in place, sponsors of Phase 1 clinical trials in the USA can ensure that their trials will meet all regulatory requirements and provide valuable data to support further development of their drug or device.

There are two main types of INDs:

• Commercial IND: 

These are submitted by sponsors with the intent to commercialize the product at a later stage

• Research IND:

These are submitted by investigators or research institutions that do not intend to commercialize the product

• Emergency use IND:

Allows FDA to authorize the use of a drug in an emergency for which there is no comparable treatment and that  does not follow the exact format for the submission of an IND according to 21 CFR Section 312

When do I need to submit an IND?

An IND should be submitted when planning to test a new drug in humans, when planning to use an approved drug for an indication that has not been in the approved labeling, when administered at a different dosage or by a different route of administration, and when administered to a different population (unless certain exemptions apply).

IND content and format

As of 2018, commercial use INDs must be submitted using the electronic Common Technical Document (eCTD) format for acceptability by the FDA. The eCTD attempts to harmonize marketing application structure and format in the US, EU, Japan, and other countries adhering to International Council for Harmonisation (ICH) guidelines and helps to save on paper and storage resources for documents.

INDs must contain information from three main areas: animal pharmacology and toxicology, manufacturing information, and clinical protocols and investigator information (Figure 2).

Figure 2. Information required for IND application

The eCTD format for the IND application contains 5 modules with specific information in each (Figure 3).

The information that sponsors/investigators must submit in an IND application based on 21CFR 312.23 can be arranged in the CTD format as follows and should contain:

Module 1-Regional and administrative information

• Cover letter (FDA 1571)-sponsor details, phase of clinical trial, details about clinical trial investigators and monitors, contract research organization (CRO) details, IRB information
• Table of contents-introductory statement and general investigational plan, along with information on previous human experience with the drug, investigational marketing experience and withdrawal information (if applicable) and plan for investigation for one year
• FDA 3674-certification of compliance with requirements ClinicalTrials.gov data bank
• Labeling-a copy of all labels and labeling to be provided to each investigator
• General Investigational Plan-contains information about the drug such as structural formula, pharmacological class, dosage form and dose, route of administration, and duration of trial
• Investigator’s brochure-contains information on the drug substance and formula, summary of pharmacological and toxicological effects in animals and humans (if known), summary of pharmacokinetics and biological disposition in animals and humans (if studies), safety and effectiveness in humans from prior clinical studies, possible risks, side effects, and precautions or special monitoring as per expected adverse events based on prior experience with the drug or similar drugs

• Module 2-Summaries

  • Quality overall summary-this includes information about the drug substance such as general information (nomenclature, structural formula), manufacture, characterization, control of drug substance, reference standards or materials, container-closure, and stability. Drug product data must contain description, pharmaceutical development, manufacture, control of excipients and drug product, reference standard or material, container-closure, and stability.
  • Nonclinical overview-the aim of this section is to present data to ensure the safe use of the experimental drug in humans taking the pharmacological, pharmacokinetic, and toxicological studies into consideration.
    • Pharmacology and pharmacokinetic studies: include pharmacokinetic, toxicokinetic, and metabolism studies with the methods used and analytical methods. Interspecies comparisons of metabolism and pharmacokinetic parameters (AUC, C_max), and limitations for extrapolation of animal data to humans should be discussed.
    • Toxicology studies: onset, severity, and duration of toxic effects, dose-dependency, reversibility (or irreversibility), and species and gender differences. Genotoxicity, carcinogenicity, toxic signs, causes of death, pathologic findings, pre- and postnatal toxicity, safety of drug during pregnancy and lactation, and local tolerance. Information Type of animal species, number of animals, route of administration and dosages, duration of treatment, systemic exposure should be included.
  • Nonclinical summary-this includes written and tabulated summaries for pharmacology, pharmacokinetic, and toxicology studies
  • Pharmacology written summary and tabulated summary-primary pharmacodynamics studies with other drugs in the class, secondary pharmacodynamic studies summarized by organ systems, safety pharmacology studies, pharmacodynamic drug interactions. The tabulated summary should contain information organized into sections such as test system, method of administration, dose, species/strain, gender, and organ systems evaluated, etc.
  • Pharmacokinetics written summary and tabulated summary-method and validation parameters for analytical procedure used for biological samples in the study, absorption studies (in vitro extents and rate, BA/BE studies), distribution studies (tissue distribution, protein binding, and placental transfer studies), metabolism studies (metabolic pathways, pre-systemic metabolism, P450 in vitro studies, enzyme induction and inhibition), excretion studies (route and extent, excretion in milk), pharmacokinetic drug interactions. The tabulated summary should include data under the following headings species, vehicle/formulation, gender, dose, method of administration, sample, analyte, assay, feeding condition, and sampling time(s).
  • Toxicology written summary and tabulated summary-single-dose toxicity (species, route), repeated-dose toxicity (species, route, duration), genotoxicity (in vitro mammalian and non-mammalian system, in vivo mammalian system), carcinogenicity studies (long-term and short-term), reproductive and developmental toxicity, local tolerance, and other studies (immunogenicity, antigenicity, dependence, studies on impurities/metabolites). Tabulated summaries should include the species/strain, dose, route of administration, duration, observed maximum non-lethal dose, and any noteworthy findings.
  • Clinical overview-includes the product development rationale (pharmacological class, target indication, current major therapies, summary of ongoing and planned clinical studies), biopharmaceutics (bioavailability issues related to formulations), clinical pharmacology (pharmacokinetics: comparative PK related to intrinsic and extrinsic factors, absorption, protein binding, metabolic pathways, pharmacodynamics: mechanism of action and receptor binding, PK/PD relationships, genetic differences, immunogenicity and clinical microbiology), efficacy data (relevant patient population, study design, end point(s), controls, statistical methods), safety (adverse effects and monitoring, animal toxicology, overdose reactions), benefits and risks.
  • Clinical summary-This section generally includes a tabulated summary and comparison of individual studies related to biopharmaceutics and analytical methods, clinical pharmacology, clinical efficacy, and clinical safety.

• Module 3-Quality

This module contains chemistry, manufacturing, and controls data for the drug substance and drug product.

• Drug substance-general information (name, manufacturer), nomenclature (CAS no., chemical name), structure (formula and stereochemistry), general properties (pH/pKa, solubility, melting point, hygroscopicity, polymorphic form), manufacturer’s name and address, description of manufacturing process and controls (schematic flow diagram of process, raw materials, catalysts, solvents, pH, critical steps, equipment, and operating conditions), control of raw materials and solvents, control of critical steps and intermediates with acceptance criteria process validation and evaluations, and manufacturing process equipment. Specification criteria for drug substance, analytical procedures and validation criteria, batches and batch analyzes, and specification, reference standards and materials, container-closure system description, and tabular listing of stability protocol and studies
• Drug product-description of drug product, dosage, composition, type of container system, drug substance, excipients, formulation development, results from in vitro/in vivo comparative studies, physicochemical and biological properties relevant to performance (pH, dissolution, particle size, flow properties, rheology, potency, polymorphism, biological activity, etc.), manufacturing process development (key validation parameters), container closure systems microbiologic attributes, compatibility, batch formula, description of manufacturing process and controls, process validation, excipient controls, stability data (stress testing, photostability tests)

• Module 4-Nonclinical study reports

This section involves the organization of nonclinical study reports which include pharmacology (primary and secondary pharmacodynamics, safety pharmacology, and pharmacodynamic drug interactions), pharmacokinetics (analytical methods and validation reports, absorption, distribution, metabolism, excretion, pharmacokinetic drug interactions), toxicology (single-dose, repeat dose, genotoxicity, carcinogenicity, reproductive and developmental toxicity, local tolerance, and other toxicity studies such as antigenicity, immunogenicity, tolerance, immunotoxicity, etc.), and literature references.

• Module 5-Clinical study reports

This section involves the organization of clinical study reports which include biopharmaceutic study reports (bioavailability study, comparative BA/BE studies, In vitro-in vivo correlations, bioanalytical and analytical methods), PK study reports (plasma protein binding, hepatic metabolism and drug interactions, human biomaterial studies), human PK studies (healthy subject and patient PK and tolerability reports, intrinsic and extrinsic factor PK reports, population PK reports), human PD reports (healthy subject and patient PK/PD reports), efficacy and safety reports (controlled and uncontrolled clinical study reports,), reports of post-marketing experience, case report forms and individual patient listings, and literature references.

IND Submission Process to the US FDA

An IND can be submitted by the sponsor/investigator at any phase of the clinical trial stage but must be submitted prior to testing the experimental drug in human participants. Figure 4 shows the steps for submission of the IND application to the FDA using the eCTD format for electronic submissions.

Figure 4. Submission process to FDA using the electronic system for INDs

Following receipt of the eCTD submission to the FDA, the FDA has a 30-day period to respond. The FDA can be in constant communication during this period to clarify any concerns or doubts about the study.  If there is no response from the FDA during this window, the study can proceed. Otherwise, the FDA can place the study on partial hold or clinical hold which can be due to inadequate data in the submitted IND or safety concerns. It is the responsibility of the sponsor/investigator to address questions that the FDA has posed and respond to these in a separate submission to the FDA. The FDA can either lift the clinical hold allowing the clinical investigation to proceed, place the study on partial hold (with certain restrictions), or continue the hold.

In addition to submitting the initial IND, the sponsor/investigator must keep the IND current and submit any amendment to the IND such as protocol amendments, safety reports, and IND annual reports.

Thus, a thorough and clear understanding of the requirements for an IND especially in the eCTD format that is recommended by the FDA is necessary to maximize chances for a smooth transition of experimental drug to the clinical trial phase. Furthermore, reviewing the FDA submission process and maintaining contact with the FDA is essential in updating the IND and protecting patient safety in case of any adverse events or protocol deviations.

References

• Understanding FDA Regulatory Requirements for Investigational New Drug Applications for Sponsor-Investigators – PMC (nih.gov)
• M4E(R2): The CTD — Efficacy Guidance for Industry (fda.gov)
• Quality Overall Summary (QOS) in eCTD format (triphasepharmasolutions.com)
• Investigational New Drug (IND) Application | FDA
• Submit Using eCTD | FDA

A lot has changed over the past few decades in the way clinical trials are conducted. Advances in data management systems, risk-based monitoring, pharmacovigilance, electronic databases, and application of complex statistical techniques for data analysis are some of the ways in which progress in clinical trials have been made. Until the mid-1990s most big- and mid-sized pharma companies carried out their own clinical trials to place their new chemical entity (NCE) on the market.

However, a gamechanger that the clinical trial industry has seen particularly in the past few decades is the advent and rise in ‘outsourcing’ of trial activities. The term ‘outsourcing’ from a clinical trial perspective refers to the delegation of duties involved in the conduct of trials and related activities by the pharmaceutical or medical device company (sponsor) to contract research organizations (CROs).

Contract research organizations (CROs) are service organizations that provide support to the pharmaceutical, biotechnology, and medical device industries in the form of research services outsourced on a contract basis. Today most activities that can be potentially done by a pharmaceutical company can be outsourced to CROs. These activities include preclinical testing of drugs or devices, synthesis of compounds and biochemical assays, and clinical trial services.

Clinical CROs focus on clinical trial services such as medical writing, data analysis, obtaining regulatory approvals and regulatory filing (1). The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guideline defines CRO as a person or organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor’s trial-related duties and functions. (2). Figure 1 shows the spectrum of activities that can be conducted by a clinical CRO.

Figure 1. Outsourced activities to a clinical CRO

An important indicator of the adoption of the outsourcing model by pharmaceutical companies is the projected rise in the CRO services market from USD 53.2 billion in 2021 to USD 86.5 billion by 2026 which is primarily due to an increase in research and development (R&D) activities and clinical trials, and increased prevalence of rare and orphan diseases (3). The coronavirus outbreak in 2020 also led to increased pharmaceutical company-CRO partnerships to expedite R&D activities for development of vaccines, drugs, and diagnostics (3). An analysis in 2017 showed that on an average 64% of clinical development services (including early phase and Phase I-IV clinical trials, clinical data management) are outsourced with only 38-40% carried out in in-house proving that the outsourcing and strategic alliances are being widely used in the clinical trial arena (4). The US government estimated that approximately one-third of trials sponsored by the 20 largest pharmaceutical companies were conducted in foreign sites (5).

Drivers for clinical trial outsourcing from a US perspective: In-house vs Outsource

The key motivators for clinical trial outsourcing for large and mid-size pharmaceutical companies include downsizing and cost-cutting, CRO expertize in a particular therapeutic area or market in which the company has lack of experience regarding regulatory processes, operational expertize , and ability to use manpower for other activities during periods of increased workload.

• Outsourcing to CROs helps retain employees that are needed for other activities while decreasing the workforce and thus saving on salaries, overhead expenses, and infrastructure costs. This helps pharmaceutical companies save a considerable amount of money and decrease the burden on employees particularly at times where there is an increased workload.
• With the globalization of clinical trials and the need to perform multinational center  trials often in countries where the company has little or no expertize regarding the regulatory landscape, CROs can help by providing local vendors to coordinate
  trial-related activities. It is usually not feasible for sponsors to take on responsibilities for all activities and CROs can help bridge the gap between sponsors and local regulatory authorities to facilitate smooth functioning of the clinical trial and help hasten drug approval.
• CROs can provide knowledge and expertize in therapeutic areas that the sponsor may not necessarily have which can allow for better management and design of the clinical trial. Additionally, CROs can also help recruit key opinion leaders (KOLs), physicians, and provide access to trial sites that are trained and experienced in a particular therapeutic area.
• CROs can provide access to ethnically diverse patient pools in different geographical locations which is necessary in some trials to understand drug efficacy.

From the perspective of US-based companies, outsourcing of clinical trials to other locations is largely driven by factors such challenges in patient recruitment and retention, high costs and lengthy regulatory timelines.

• Patient recruitment to obtain a suitable population size is necessary to obtain results from a trial that are both clinically and statistically meaningful. The inability to recruit patients that represent diverse classes such as women, ethnic minorities, and elderly and pediatric  populations can result in delays in drug approvals. In the US, low populations of test subjects and unwillingness to volunteer is based on hesitation on the part of patients and their physicians to participate in trials due to increased workload and costs. The limited availability of KOLs willing to volunteers in trials is also lower in the US. Furthermore, it may be increasingly difficult to find appropriate subjects especially in cases of rare diseases or conditions in which the screening failure rate is high due to smaller patient pool.
• An obvious reason that companies may choose to conduct trials outside the US is cost. Recruitment, staff, administrative, insurance, resource, and infrastructure costs are much higher in the US compared to developing countries making outsourcing an attractive financial option. It is estimated that conducting a clinical trial in India costs approximately 60% less than in the US which is a significant financial advantage.
• Outsourcing helps pharmaceutical companies navigate complex regulatory pathways that can increase timelines for drug approval while placing a significant financial burden on the company. Multicentre trials benefit from local CROs that understand the regulatory requirements of the region. Since the process for drug approval by the US Food and Drug Administration (FDA) is a lengthy process, outsourcing can help shorten timelines as the CROs can facilitate faster approvals.

Although conducting clinical trials outside the US represents an attractive option both financially and logistically for pharmaceutical companies some challenges remain with the outsourcing model. Regulatory requirements such as Institutional Review Board (IRB) approvals, import licensing, and contract negotiations can differ between countries even in the same region making it necessary to choose an appropriate CRO that has a thorough understanding of these processes. It is important to ensure that the standard of care that the subjects receive in developing countries is on par with what would be provided to subjects in the US.

Protection of data integrity is also a concern when trials are carried out in rural areas along with poor infrastructure and logistics which may hamper transportation of the investigational drug and patient samples compromising trial data. Inability to adequately monitor clinical trials by local Institutional Review Boards (IRBs) due to financial constraints in developing countries may jeopardize participant safety. Furthermore, all studies carried out at foreign sites must comply with FDA regulations, be carried out in accordance with Good Clinical Practice (GCP) guidelines, and FDA should be able to validate the data through an onsite inspection. The benefits and risks associated with outsourcing should be evaluated when considering outsourcing.

Tips to select an appropriate CRO partner

The successful conduct and completion of a clinical trial in a timely and cost-effective manner hinges on the selection of a CRO by the sponsor that meets their needs. Some points to keep in mind when vetting CROs include:

• CRO experience in the therapeutic or geographic area where the clinical trial is to be conducted, ability to handle roadblocks that may occur such as site selection, patient recruitment and retention, and data management, relationships with KOLs and sites for conducting the trial, more information about the CRO can be obtained from client references.
• Quality management systems of the CRO-appropriate training of staff on quality management to comply with regional and global regulations, transparency of operating systems related to activities such as data security, and certificates on quality assurance should be provided by the CRO.
• CRO size: consideration of the CRO size is important depending on whether the sponsor is a small, mid, or big pharmaceutical company. Large CROs may be experienced but may be more costly and will not be able to give much attention to the project whereas smaller CROs can provide customized services with a greater focus on the client.
• Price of services: this is one of the most important factors as all pharmaceutical companies have a budget allocated to clinical trials. In addition, a breakdown of costs is necessary for each activity as bundled costs may not consider any unforeseen expense which could accumulate.
• Employee experience, training, qualification and CRO staff turnover are pivotal to the success of a trial.
• Accessibility: an appointed point of contact or a team that the sponsor can communicate with easily in case of any problems is essential to avoid major hurdles that can jeopardize trials.

Management of outsourced trials by sponsor

To avoid misunderstandings and maintain a healthy sponsor-CRO relationship, it is important that CROs and their outsourced activities are appropriately managed. Although a clinical trial may be outsourced to a CRO, FDA regulations require that the sponsor is responsible for the oversight of the trial. Some ways in which sponsors can manage CROs are:

• Develop comprehensive contractual agreements between the sponsor and CRO that outlines activities and responsibilities to be performed by each entity in a detailed manner. This contract should include financial, logistical, and legal responsibilities as well as audits and meeting schedules, quality measures, and schedules for completion of tasks and deliverables. This is a time-consuming task but should be outlined at the outset to avoid confusion and unnecessary delays.
• Creating a statement of work that defines the roles and responsibilities of the sponsor and CRO at each stage of the clinical trial will help avoid replication of activities by either party and allow the sponsor to take full benefit of the capabilities of the CRO. Every task along with a succinct description should be presented by the sponsor based on their expectations from the CRO without leaving anything open for interpretation.
• Schedules are necessary for timely completion of goals and milestones and can be provided in the form of Gantt chart for the project. Agreement on timelines is important.
• Regular meetings either in-person or virtually should be conducted and any problems or unforeseen issues should be discussed. It is important to keep the lines of communication open between the sponsor and CRO by appointing a person/team to be available for discussions if the need arises.
• A thorough understanding of the sponsors or CROs standard operating procedures (SOPs) is important. If the sponsors SOPs are being used it is necessary to maintain a training record to ensure that the CROs employees are well-versed with the SOPs. Staff should also be kept updated with any new quality system or GCP guidelines and these records should also be documented.
• Make sure ‘must-have’ expectations are specified to the CRO as time and resources are usually limited which will help CROs to avoid focusing on smaller, insignificant tasks.
• Sponsors should consider performing audits at trial sites to ensure compliance of the CRO with quality standards and documentation and gain an understanding at the ground level. It helps the sponsor understand whether the CRO staff can tackle problems and if the necessary corrective and preventative actions (CAPA) were taken. The timing of an audit is important as it should be done when enough subjects are enrolled but enough time is still left so any necessary changes can be made.
• Maintaining a professional relationship by understanding staff in each team and their expertize is necessary to ensure the success of the sponsor and CRO. Communication, trust, and agreement are key factors that should be kept in mind during any project.

US FDA oversight of outsourced clinical trials

In addition to management of CROs and outsourced activities by sponsors, the US FDA is responsible for overseeing the operations of clinical trials, both domestic and foreign, that are conducted in support of a future application for a new drug approval in the US. The FDA’s Office of Regulatory Affairs (ORA) has a Bioresearch Monitoring (BIMO) program which is implemented through multi-center compliance programs to ensure protection of rights, safety, and welfare of human subjects involved in FDA-regulated clinical studies (6).

ORA inspectors are required to conduct inspections to ensure:

• Compliance with applicable statutory and regulatory requirements
• Assure reliability of the study data
• Ensure that ethical and scientific standards are maintained during the clinical study

All activities even if outsourced to a CRO must be carried out in accordance with the protocol and investigational plan, GCP, and applicable FDA regulations.  Inspection of CRO for outsourced activities by ORA investigators include (6):

• Evaluations of SOPs and work instructions developed by the sponsor and criteria for selection of CRO based on compliance with FDA regulations and GCP standards and provision of preferred vendor lists (if any).
• Detailed analysis of written agreements (master service agreements, statements of work and quality agreements) for critical steps in the trial to determine if roles, tasks, and responsibilities of sponsor and CRO are clearly defined, and which party is responsible for final decision-making for various steps of the trial.
• Determination of CRO employee qualifications and training records.
• Review of SOPs of either the sponsor or CRO depending on which one was followed including any deviation plans and records in case deviations occurred for documenting and rectifying them (CAPA). SOPs to be studied include those for audits, communications plans, escalation plans, and contingency plans.
• Review of sponsor-CRO communications to determine frequency, type, focus, and documentation of meetings.
• Ensure provision of protocol-specific training to CRO.
• Determination of sponsor’s oversight of activities outsourced to CRO through audit reports, if necessary.

The basic tenet of clinical trials is to protect the safety and welfare of human subjects along with providing meaningful data to support the efficacy of new drugs. This makes it important for CROs to comply with FDA regulations and GCP guidelines to facilitate approval of new drugs in the US market. Outsourcing clinical trials can be a win-win situation for the sponsor and CRO if there is adequate oversight and management of CROs by sponsors and FDA and mutual trust.

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References

• Landhius E. The rise of outsourcing. Nature 2018; 556: 263.
• E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) Guidance for Industry, March 2018.
• Contract Research Organization Services Market – Global Forecast to 2026 | Markets and Markets
• PAREXEL Biopharmaceutical Sourcebook 2016/2017, Beroe Analysis
• The Ethical Implications of the Global Outsourcing of Clinical Research – Public Citizen
• Food and Drug Administration Compliance Program Chapter 48: Bioresearch Monitoring (Program # 7348.810)

­­Drug development strategy for US FDA

It takes a staggering 12 years on an average for a drug to travel from the laboratory bench to your bedside! This is coupled with up to approximately $1 billion in research and development costs that a pharmaceutical company needs to spend to bring its potential molecule to market. Furthermore, only about 10% of drugs that enter Phase I clinical trials are granted marketing approval by the Food and Drug Administration (US FDA). FDA is the regulatory body that handles drug approvals in the United States and has the world’s most stringent standards for approving drugs. The drug development process is well-defined and compartmentalized into logical stages starting from discovery to commercial use enabling companies to utilize this as roadmap when developing a drug.

The drug development process in the US is commonly divided below 5 stages:

The various activities in each stage of the drug development process are as follows:

1. Discovery and Development: Target and hit identification and optimization, assay development and validation, lead optimization, ADME, mechanism of action, dose and route of administration, drug interactions, effects in subgroups (gender, age, ethnicity, etc.)
2. Preclinical research: In vivo animal studies, in vitro and ex vivo assays, formulation optimization, bioavailability, drug delivery, dose findings range
3. Clinical research: Phase I (20-100 healthy volunteers or people with disease/condition, safety and dosage), Phase II ( ̴100 people with disease/condition, efficacy and side effects), Phase III (300-3000 volunteers with disease/condition, efficacy and monitoring of adverse reactions), Phase IV (several thousand volunteers who have disease/condition, safety, and efficacy)
4. FDA review: New Drug Application (NDA), Abbreviated New Drug Application (ANDA), Biologics License Application (BLA) is filed by the company, FDA review, FDA approval
5. FDA post-market safety monitoring: Collection of data on adverse events and untoward effects of drug

Of all stages in drug development, the clinical research stage is often the most laborious, expensive, and time-consuming and can last up to 7 years. Additionally, only 25-30% of drugs make their way from Phase I to Phase III trials.

What is the reason for this high attrition rate?

Often, regulatory agencies are blamed for failure of drugs to reach the market. However, poor planning (or in some cases, no clinical development plan at all) by pharmaceutical companies also contributes to failure to achieve marketing approval.

So, what can pharmaceutical companies do to boost their chances of success?

The answer is simple: develop a Target Product Profile (TPP), the heart of the drug development strategy

The adage “Well begun is half done” is usually a good point for pharmaceutical companies to consider when embarking on their drug development journey, which typically begins with the development of a TPP.

In 2007, the FDA released a draft guidance recommending the use of TPP as a strategic development tool to facilitate and streamline discussions between the Sponsor and the FDA, minimize the risk of late-stage drug failure, and allow for optimal safety and efficacy data to be available in a timely manner. Breder et al. showed that drugs and biologics approved by the FDA that used TPPs were associated with more efficient regulatory review times.

The TPP is basically a dynamic blueprint for the drug development process and provides a statement of the overall intent of the drug development program. Commercial goals of the product, pharmacology, and practicalities of clinical development should be considered when developing a TPP. Input from various stakeholders including regulatory, clinical, preclinical, marketing, research and development (R&D), and commercial teams is essential for formatting a TPP.

A TPP for a drug product generally includes the following:

1. Indications and usage
2. Dosage and administration
3. Dosage forms and strengths
4. Contraindications
5. Warnings and precautions
6. Adverse reactions
7. Drug interactions
8. Use in specific populations
9. Drug abuse and dependence
10. Overdosage
11. Description
12. Clinical pharmacology
13. Nonclinical toxicology
14. Clinical studies
15. References
16. Storage and handling conditions
17. Patient counseling information

Clinical Development Plan (CDP)

Various strategies and plans are centered  around the TPP that culminate in the clinical development plan (CDP). The CDP is founded on the goals stated in the TPP and presents the plan to achieve them.

The clinical development plan (CDP) should include:

• Regulatory strategy

In addition to a thorough understanding of the regulatory landscape of the country in which the drug product is intended to be marketed, a comprehensive regulatory plan is essential for the smooth movement of the product through approval phases. A regulatory strategy should include:

1. Pathway for regulatory approval
2. Differentiating features of the product compared to other products in terms of labeling
3. Guidelines, both global and local, that are applicable to the drug product development program
4. Target timelines for regulatory submissions at different stages of product development (Pre-IND and NDA submissions)
5. Well-developed plan for interaction with regulatory agencies/health authorities-what needs to be submitted at each stage, potential questions
6. A thorough understanding of the format for regulatory submissions (electronic format as per FDA guidance document released in July 2021.
7. Category of regulatory submission depending upon product characetristics: Investigational New Drug (IND) application or New Drug Application (NDA) regulatory pathway (505 (b)(1) or 505(b)(2))?
8. Due diligence on regulatory pathway for similar drugs and their stage of development and approval
9. Options available for registration such as fast-track approvals, orphan diseases, etc.
10. Information on studies and data needed at each stage of drug product development for regulators to allow progress to the next stage

• Nonclinical studies

Data from nonclinical studies are used to inform the design of clinical trials and is needed for regulators to ensure that drug is suitable to test in humans. These studies involve in vitro or ex vivo studies and animal studies and are carried out in accordance with ICH and Good Laboratory Practice (GLP) guidelines. Nonclinical studies plan should include:

1. Choice of animal species (rodent and non-rodent)
2. Tissue or cell culture methods for ex vivo studies
3. Dose selection, frequency, and route of administration
4. Analytical methods and validation parameters
5. Toxicity studies-reproductive, carcinogenicity studies, genotoxicity, etc. and single-dose or multiple-dose studies
6. Design of pharmacokinetic (PK) studies and ADME studies

• Clinical studies

The clinical research phase (Phase I, II, and III studies) is the most laborious, expensive, and time-consuming step in the clinical development program. Despite the large investment in time and money spent on this phase, only 25-30% of drugs move from Phase I to Phase III. Clinical studies are essential to ensure the safety and efficacy of the drug in humans which is pivotal to its chances of success and therefore sufficient details for each phase are necessary.

The clinical trials design for each phase should include the following details:

1. Study participants (gender, age, ethnicity, co-morbidities, etc.)
2. Subject inclusion and exclusion criteria
3. Trial design (parallel, crossover, factorial)
4. Subject size calculation
5. Control group (placebo, no comparator, active control)
6. Design based on hypotheses (superiority, noninferiority, equivalence)
7. Study endpoints: safety, efficacy, PK/PD parameters, patient-reported outcomes, biomarkers
8. Dose and frequency of administration
9. Dosage form and strength, route of administration
10. Duration of treatment
11. Resources needed for trial management and clinical supplies
12. Schedule or timeline for completion of studies
13. Resource allocation and investments
14. Statistical analysis plan (details on type of statistical tests to be used, significance levels, software details)
15. Risk evaluation and management strategies (REMS) and pharmacovigilance plans to monitor any post-approval safety concerns

• Chemistry, manufacturing, and controls (CMC) studies

CMC activities ensure that a drug or product is safe, effective, and consistent between batches. These activities encompass characterization of the drug, manufacturing processes, drug product development, and scale-up to ensure that a reproducible molecule is available for clinical studies and commercial supply.

The following items should be included in a CMC plan:

1. Drug and product development: synthetic routes to produce the drug, description of the chemical and physical properties of the drug such as pKa, solubility, melting points, spectral properties, log P (lipophilicity), polymorphs, etc., analytical method development and validation for quantification of drug and impurities or related substances, raw materials, drug, and excipient(s) sourcing and vendor supplies, formulation development: dose strength, formulation, and route of administration, stability protocols
2. Quality related activities: quality control and in-process and finished drug/product inspections and tests, validation activities (sterility, cleaning), audit plans, quality management system development
3. Clinical trial material: packaging and labeling of clinical trial material, storage, and transport conditions for clinical trial material
4. Manufacturing process: validation, supply of labeling, vendor qualifications, scale-up and technology transfer

• Commercial strategy

Although obtaining regulatory approval for a drug is a major feat for a pharmaceutical company it does not necessarily ensure commercial success in terms of sales and return on investment. Barriers to commercial success include competitive landscape and pricing, access challenges, and increased expectations by patients, physicians, and caregivers. A commercial strategy helps facilitate interactions with regulatory authorities and serves as a business tool for discussions with investors, partners, employees, physicians, and payors.

A comprehensive commercial strategy should include:

1. A thorough analysis of the competitive landscape of the product with existing treatments in terms of efficacy, adverse effects, costs, patients, and physicians’ satisfaction
2. Product differentiation in terms of outcomes and quality
3. Information on pricing and reimbursement
4. Understanding clinical and market needs (market size)
5. Market research on optimal characteristics of the drug from key opinion leaders such as physicians and payors
6. Health economic aspects such a trial endpoint, and real-world evidence (patient registries and databases) to ascertain the drugs economic benefit

The approval and commercial success of a new drug is an interplay of several factors: clinical, nonclinical, commercial, regulatory, and CMC. Starting off a drug development program ‘right’ with the construction of a TPP sets a strong foundation for further strategic development and planning in the above areas to allow for a smooth launch of a drug. This not only assures interaction with regulatory authorities but also keeps internal company functions aligned with meeting predetermined product goals.

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References:

1. Woulters, O.J., McKee, M., Luyten, J. Estimated research and development investment to bring a new medicine to market, 2009-2018 JAMA 2020. 323: 844-853.
2. https://www.fda.gov/patients/learn-about-drug-and-device-approvals/drug-development-process 
3. Breder, C.D., Du, W., Tyndall, A. What’s the regulatory value of a target product profile? Trends in Biotechnology 2017. 35 (7): 576-579.
4. Singh, G. Target Product Profile and Clinical Development Plan. Pharmaceutical Medicine and Translational Clinical Research 2018. 65-80
5. Clinical Development Plan Guide 110613 (biostrategics.com)
6. Target Product Profile-A Strategic Development Process Tool. Draft Guidance March 2007

Foreign Clinical Trials (FCTs)

Prior to the 1962 Kefauver-Harrison Amendments, it was uncommon for a Sponsor to submit FCTs data. In 1975 provisions that permit the submission of FCTs data not conducted under an IND were codified in 21CFR312.120. Since then, medical product discovery & development have become increasingly globalized. In the past three decades, drug development, production & distribution moved from a national and regionally‐ centered activity to a global one. This increase in shift has significant implications on FDA’s perspective on international clinical trials.

International Clinical Investigators & Clinical Trials

Figure 1 – Rate of Increase for FDA Regulated Investigators: 1996-2006

During the 10-year period(1996 to 2006), the % of the total for U.S. based investigators declined by 20% (annual growth rate 1.8%). The number of active FDA–regulated investigators who are based outside the United States has grown.

Figure 2 – Rate of Increase for FDA Regulated Investigators: 2000-2014

OIG Report:

Over half of all clinical trial sites are outside the U.S. % of non -U.S. clinical investigators conducting trials under INDs has doubled over the last decade. 80 % of applications for drugs & biologics contain data from ex -U.S. studies. 78 % of all subjects were enrolled outside the U.S. 87 % of all subjects in recent biologics trials were enrolled outside the U.S.

Distribution of Studies

Figure 3 – All studies registered on ClinicalTrials.gov: Data as of July 08, 2021

Figure 4 – ClinicalTrials.gov currently lists 174,156 studies with locations in 187 countries

What Drives Companies to Conduct Clinical Trials Outside the USA?

Pushing & Pulling Forces

Figure 5

Figure 6 – Number of Registered Studies Over Time

Current Law Governing Foreign Clinical Studies:

• Foreign Study Conducted Under IND Application.

When a study is conducted under an IND but is located outside of the United States, the study still must comport with all relevant FDA regulations as if it were being conducted within the United States. A Sponsor is not required to conduct an FCT under an IND in order to use it as support for an NDA or IND.

• Foreign Clinical Trials Not Conducted Under an IND.

Acceptance of Foreign Clinical Data: FDA Accepts Foreign Clinical data from studies not conducted under an IND if the following conditions are met:

1. Study was conducted in accordance with Good Clinical Practice (GCP).
2. FDA is able to validate the data from the study through an onsite inspection.

GCP:

Sponsor shall submit to FDA a description of actions taken to ensure research conformed to GCP: – Defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data &reported results are credible and accurate and that the rights, safety, and well-being of trial subjects are protected.

Supporting Information:

1. CI’s qualifications.
2. Description of the research facilities.
3. Summary of the protocol & results of the study &, should FDA request, case records
4. Description & details of the product/drug used.
5. Information showing that the study is adequate & well controlled.
6. Name & address of the IEC, a summary of the IEC’s decision.
7. A description: – how IC was obtained – what incentives, if any, were provided to subjects in the study – how the sponsor(s) monitored the study – how CIs were trained to comply with GCP.

Validation of Data: Onsite Inspections

• Help to ensure the protection of rights, safety and welfare of research participants.
• Help to ensure data that are submitted in marketing applications are fit for the purpose

For regulatory decision making (Approval)

As the evidence base for clinical use of the drug (Label)

• Allow evaluation of compliance with FDA regulations.

Assigning International Inspections

Clinical sites likely to be audited when: – only foreign data are submitted to support an application – insufficient domestic data – domestic and foreign data show conflicting results pertinent to decision-making – there is a serious issue to resolve (e.g., suspicion of fraud, scientific misconduct, significant human subject protection violations).

Useful Guidance

FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND Frequently Asked Questions – Issued March 2012 – Provides clarifications for sponsors and applicants on how to demonstrate compliance with the requirements of 21 CFR 312.120.

The challenges

• Increase in Breadth of Inspections.
• Increasing volume to data from other regions submitted in support of marketing submissions submitted to FDA.
• Increase in the breadth of international inspections.

Figure 7 – Distribution of Subject  Enrollment

Finite inspection resources:

The breadth of international inspections coupled with finite inspection resources results in the inspection of a limited number of sites. Despite the large portion of clinical studies being conducted abroad, the OIG 2010 Report found that the FDA only inspected 0.7% of all foreign clinical sites in 2008, compared to 1.9% of all domestic clinical sites.

Figure 8

Strategies

Leveraging Knowledge/ Resources:

• Utilize finite resources strategically and efficiently and leverage inspection – EMA-FDA Collaboration GCP Inspection Initiative
• Initiated in Sept. 2009 as a pilot to
• Develop a joint GCP program – Plan, coordinate, schedule, and conduct collaborative GCP inspections
• Establish joint procedures – Share information related to drug applications – FDA International Offices:
• Provide a platform for inspection of foreign facilities.
• Offices collect & leverage local & regional knowledge.

Building Quality:

Build quality during the planning stages: – incorporate quality management approach into clinical studies & their oversight to prevent the critical/errors, and monitor for those errors (perhaps centrally (remotely/real-time)) and focus less on the less important matters.

Utilize Data Standards:

• Encouraging sponsors to utilize data standards to improve analysis and site selection for inspection.
• Risk-Based Monitoring and Inspection – Using innovative strategies & tools to identify sites for clinical inspection(ex. GCP risk-based site selection tool for clinical inspection).

Science-Based Standards:

• Working to converge regulatory standards (to share a common foundation of science-based goals for product safety, quality, and efficacy). – Continue to work to converge regulatory standards, processes, and procedures for the pharmaceutical industry( ex. ICH, ICH Global Cooperation Group Members).
• Strengthening the regulatory capacity of governments to manage, assess, and regulate drug development ( such as providing information, tools, training & exchange programs).

References:

• https://clinicaltrials.gov/
• https://www.fda.gov/regulatory-information/search-fda-guidance-documents
• https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-classification-database