Stakeholders in Drug Development (1/6 Drug Development Explainer Series)

Author Note: This series was written in collaboration with James Smith and Kirsten Angeles.

Overview

There are many layers to drug development, from clinical trials to chemical compounds, to long lists of regulations… But, at the centre, you’ll find people—teams of experts and individual patients, each playing a part in a complex symphony of innovation and regulation.

The interactions of these stakeholders are governed by regulatory frameworks ensuring checks and balances at every stage. The system is designed with the intention that it will lead to good results and is not dependent on a single company or even individual doing a good job – whether it’s guidelines made by regulatory bodies, how sponsors qualify their vendors, the involvement of independent expert boards, or routine audits and inspections.

Working and maintaining good relationships with these varied, important stakeholders is critical for a drug developer. In the following sections, we discuss the key stakeholders, the people involved, and how you might contact them. 

Note: The focus of this piece is on “regulated” stakeholders leading up to approval. Obviously other players that we don’t discuss here play important roles too, e.g. people who take part in trials and purchase the drug, medical journals that publish research studies, and downstream entities like pharmacies that sell the drug.

Regulatory Bodies

The foundation of the drug development process is the regulatory framework provided by national and international organisations. 

The World Health Organization (WHO),the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) play significant roles in standardising practices across countries. This standardisation is intended to make it easier for drugs to reach a global market.

• The WHO develops norms, standards, and guidelines to promote pharmaceutical quality assurance as part of its Constitution. For instance, it published its Laboratory Biosafety Manual in 1983, which is updated regularly and guides biosafety standards globally. 
• The ICH defines guidelines that are then implemented as laws in respective countries, providing the boilerplates for regulation. An example is the Good Clinical Practice (GCP) guideline (ICH E6), which sets international standards for clinical trials involving human subjects and is widely adopted by regulatory agencies worldwide.

Based on the WHO and ICH standards (such as GCP for clinical trials and Good Manufacturing Practice (GMP) for drug manufacturing) and other organisations which define adjacent standards such as Good Laboratory Practice (GLP) federal agencies like the Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) in Europe establish national guidelines that dictate the proper conduct of clinical trials, manufacturing, and marketing of medical products. .

These guidelines are often not just recommendations but codified into law, requiring strict compliance. For example, in the U.S., the FDA mandates compliance with some standards in Title 21 of the Code of Federal Regulations (CFR) with regulations outlining minimum manufacturing or laboratory practices and requirements.

How do regulatory bodies oversee standards?

Regulatory agencies conduct inspections and audits of ~all the other stakeholders mentioned below. Audits are often unannounced and thorough, so it is challenging to game them. A risk-based approach is used to determine who to audit, such that facilities selected for audit have the greatest potential for public health risk should they not be compliant. This includes earlier-stage manufacturing facilities or earlier-stage companies where a problem has been reported (e.g., if there was an unexpected safety issue in a trial). The FDA inspects pharmaceutical facilities globally, including those involved in manufacturing ingredients and finished products. Inspections will often take place during clinical trials, pre-approval, and then regularly post-approval (e.g., every few years). FDA also tests some drugs in their own labs or via contractors to check that they meet the specifications they claim to/should meet (about one percent of tested drugs fail to meet the established quality specifications). After approval, safety monitoring with real-world systems comes into play (like the FDA’s Adverse Event Reporting System).

The FDA also conducts regular inspections of clinical trial sites, pharmaceutical companies, contractors, and Institutional Review Boards (IRBs) to ensure compliance with GCP guidelines. The FDA’s Office of Bioresearch Monitoring Operations (OBIMO) oversees domestic and foreign inspections for clinical and non-clinical research. In a 2022 report, they shared summaries from 766 inspections across multiple stakeholders that have to adhere to GCP, looking at failures to comply with protocol requirements, inadequate record-keeping, and lack of proper monitoring clinical investigations. IRBs were observed to have issues with meeting minutes, review procedures, and documentation. 

Non-compliance to these regulations can be costly. From 2003 to 2016, pharmaceutical companies paid fines of $33B in the US. Violations of cGMP (Current Good Manufacturing Practices, the U.S. equivalent of GCP) can result in fines and jail time. A database lists the fines paid by pharmaceutical companies since 2000 at ~$112B for 1,217 cases. Most of these were due to false promotion and were settled under the False Claims Act. A recent example of a GCP violation and its consequences was Pfizer replacing half of its trial sites in one of its vaccine trials. 

Sponsors

When discussing “sponsors” in drug development, we refer to entities which assume the task of bringing a new drug to market. These can range from a single person (e.g. investigator-initiated trials) and corporations to medical/government institutions (federal agencies like the National Institutes of Health or NIH). Pfizer and BioNTech, for example, “sponsored” the development of BNT163b2 (Comirnaty), the mRNA COVID-19 vaccine. 

How do sponsors oversee the drug development process?

In drug development, the buck stops with the sponsor – that is, the ultimate responsibility for actions or decisions lies with them, and they remain responsible for any shortcomings or defects even when tasks like manufacturing or clinical trials are outsourced to third parties – a point articulated religiously in GCP guidelines.

Sponsors, therefore, are rigorous. Their approach leans towards exhaustive planning and vigilant monitoring to ensure everything aligns with safety and regulatory guidelines. Some argue that these high standards are a convenient moat against new competitors. This may be true, but the prevailing belief among people working in the industry is that measures are in place for a good reason: protecting participant/patient safety.

Sponsors also engage in a thorough “vendor qualification” process that investigates the contracted companies’ (or vendor’s – see next section) ability to meet regulatory requirements. This review can encompass anything from answering questions to undergoing a full-scale, in-person audit. Essentially, if a vendor does not meet the requisite quality standards, they are disqualified from consideration. A typical process assesses 2-4 vendors in parallel and decides who to move forward with.

Qualification processes include:

• On-site (or remote) audits of facilities or trial sites
• Evaluation of documented quality systems, including SOPs
• Review of personnel competency and training, including through interviews with staff
• Assessment of change control processes
• Technical capability analysis
• Examination of previous quality or supply issues
• Checks against public databases in which compliance issues are reported (e.g., FDA warning letters)

Once contracted, sponsors continue to monitor their performance to ensure ongoing compliance. This is critical because if a regulatory body audits a sponsor, the scope of the audit can extend to how well the sponsor has qualified and overseen its vendors. Regulatory agencies themselves sometimes directly inspect vendors. For instance, the FDA might inspect vendors supplying active pharmaceutical ingredients (APIs) to ensure they comply with GMP standards (we discuss vendor audits below). Examples of GMP audit checklists are available here. Various checklists for GCP and other guidelines also exist. 

When a sponsor audits a manufacturing vendor, they typically spend two days inspecting the manufacturing site (e.g. looking for evidence of contamination), reviewing procedures, and interviewing key staff. FDA pre-market audits can be ~five days; they are extremely thorough. The typical process would be something like this: 

• Facility tour: walkthrough of the manufacturing, laboratory, and storage areas to observe practices.
• Document assessment: review SOPs, batch records, validation documents, quality agreements, and other essential documents.
• Staff interviews: conduct interviews with staff at different levels to assess their understanding of regulations and company policies.
• Observation and evaluation: comply with regulations like cleanliness, equipment calibration, raw material quality, etc.

Vendors

Vendors are external organisations or service providers that assist in various stages of drug development. Many aspects of pharmaceutical development are outsourced to them, particularly by smaller biotechnology companies that can’t develop sufficient internal infrastructure for large-scale drug development (similar to other industries, e.g. smartphones). Their jobs dovetail neatly – while CDMOs bring the drug to life, and CROs evaluate its efficacy with the help of study sites who enrol participants:

• Contract Research Organisations (CROs): CROs roles can be incredibly diverse, from pre-clinical research involving in vitro and animal studies to Phase I-IV clinical trials and post-marketing surveillance. Beyond doing the work, CROs bring expertise that is helpful for smaller companies without experience with drug development. They will know how to talk to regulators, and know what regulators tend to expect.
• Contract Development and Manufacturing Organisations (CDMOs): CDMOs, on the other hand, handle, as the name suggests, the manufacture of the drug and the necessary manufacturing development. The term development might seem mysterious: it means creating the manufacturing process, any tests that need to be done on the drug to check its function, quality, etc, and testing all of that out. CDMOs can provide formulation, analytical services, blending, coating, converting, packaging, serialisation and shipment, though unfortunately, a single organisation sometimes (maybe even often) can’t do everything needed. Just to give one example, Lonza, a well known CDMO, helped develop Moderna’s mRNA COVID-19 vaccine.
• Study sites: Study sites are locations where participants are recruited, and the clinical trial protocol is executed. A Principal Investigator (PI) leads study sites supported by a team of doctors, nurses, and other healthcare professionals. Typically, study sites are part of hospitals or outpatient practices, but some specialised sites exist that only do clinical trials. Recruitment usually happens at many study sites in parallel. Some study sites collaborate as Clinical Trial Network (CTN), which aims to pool resources under unified standard operating procedures and thereby streamline trial procedures.

There are also specialised contractors for all sorts of services we won’t go into detail here, such as animal testing facilities, clinical trial depots, specialised manufacturing techniques, or regulatory consulting in certain jurisdictions.

Some notes on vendors:

1. As a small biotech, your business is is not worth much to large CROs, whose main clients are big pharma, so expect to be working with their C or D teams – this means even if they have a good reputation, they might not be good for you. Working with a smaller CRO often means they are likely more invested in your project but might be unable to run larger trials later in development. It’s a bit of a trade-off.
2. All vendors can have really long waiting timelines (6-12 months for CDMOs and 1-6 months for CROs, similar scales for certain clinical trial sites).

How do vendors ensure the quality and safety of drug development?

It’s worth noting that CDMOs and CROs have an inherent economic interest in delivering services according to the sponsor’s specifications (as contractors their reputation and future business depends on delivering). Some billion-dollar company CROs even specialise in providing monitoring services for sponsors, overseeing all their vendors’ activities. So how do sponsors and vendors guarantee the quality and safety of drug development?

1. Different risk management tools are routinely employed, e.g. Failure Mode and Effect Analysis (FMEA) and risk analysis plans to foresee potential risks. 
2. To ensure accountability and compliance, every relevant action and document is time-stamped and stored for future scrutiny in a Quality Management System (QMS) to provide a transparent trail that can be audited for compliance at any time in the future.
3. When risks turn into issues, they are systematically addressed through Corrective and Preventive Measures (CAPAs). (We list some good resources to consult in another post if you want to learn more about quality management procedures.)
4. It’s worth noting that PIs are also professionally obliged to ensure that participants are cared for optimally and treated ethically. 

Independent Parties 

We just talked about how the previous stakeholders ensure and oversee quality, ethics, and safety in drug development – well, this is the sole purpose of independent parties. 

Institutional Review Boards are the first stakeholder mentioned in the GCP guidelines. In the U.S., the National Research Act of 1974 mandates IRBs for any biomedical or behavioural research involving human subjects and the FDA for any drug development in humans.

• Institutional Review Boards (IRBs): Are composed of at least five experts in pharmacology, medicine, bioethics, and patient representatives. They provide independent scientific review and ethical oversight, ensuring participants’ dignity, rights, and welfare are respected and risks minimised. IRBs, either independent or affiliated with academic institutions or hospitals.
• Monitoring Boards: In addition, monitoring committees put together by the sponsor for a single trial have become increasingly prevalent. In the simplest form, Independent Medical Monitors (IMMs) provide an independent examination of the ongoing safety events of a clinical trial. Data and Safety Monitoring Boards (DSMBs) are independent groups of experts reviewing both the safety events as well as data produced in a clinical trial.
• Scientific Advisory Boards (SABs): They form a temporary or permanent body associated with regulators or companies consisting of independent scientific experts. SABs provide independent overviews, analyses, and critiques for new technologies, approval considerations or regulatory procedures.
• Patient organisations are commonly not considered part of the formal drug development process in guidelines or law. Still, they are heavily involved in advocacy and oversight of all other stakeholders, including regulators. Examples include the Patient-Centered Outcomes Research Institute (PCORI) or public advocacy groups and non-profit watchdogs like the Public Citizen’s Health Research Group. 

How to get in touch with stakeholders?

• Regulators: Interactions with regulators are not easy to broker, and you should aim only to discuss issues with regulators that you really need to.
  • Guidance documents: The first place to look is regulatory guidance documents which describe their (sometimes remarkably specific) thinking on a topic (see the FDA Guidance Document Database for specific examples). Though technically only guidance – that is, not legally binding, assume that regulators will expect you to follow the recommendations unless you have a strong scientific justification for not doing so. 
  • Consultants: There are a lot of ex-regulators or ex-regulatory professionals from pharmaceutical companies or biotechs that you can engage as consultants. This can spare you from wasting precious time with regulators. The best way to find the specific person you need is to talk to other companies and get referrals. Check for experience with jurisdiction, indication, and modality (e.g. small molecule vs. biologic). Expect to pay between 200 and 500 USD per hour, sometimes significantly more for more senior people. 
  • Official channels: When you’re ready to interact with regulators, there are different ways of doing so depending on the country you’re targeting and the stage of development. Ensure you check early on when it’s possible to interact with regulators and aim to take every opportunity to interact with them. Some are optional (like the INTERACT meeting), while others (such as the pre-IND meeting) are essentially required.
  • There are also various regulatory conferences worth attending:
    • FDA Conferences and Workshops,
    • BIO International Convention,
    • Drug Information Association Conferences,
    • Miscellaneous other regulatory conferences

• Sponsors: Probably the most effective way of engaging with sponsors is through therapeutic-specific conferences. Ask around before booking the next conference that just ended up in your inbox – there are many conferences, and unfortunately, a large number are not valuable. JP Morgan Health Care Conference is one of many investment bank events, some of which are hard to get into.

• CROs & CDMOs: Conferences, industry directories, references (strongly recommended), or direct website outreach may work best. They are almost always eager to talk to you. Ideally, you should get to non-business development people as quickly as possible so you can evaluate their actual expertise, and bring or talk to an expert on your side to help with that evaluation.

• Study Sites: CROs will almost always be able to provide a list of study sites they have collaborated with in the past. In addition, databases such as Clinicaltrials.gov (or national equivalents) list the study sites that have enrolled participants for a given clinical trial. Beyond that, look for professional associations with member directories, look at notable faculty and alumni profiles on university and research institutions, or attend industry events where medical experts may be invited as speakers. 

• Independent boards: While directories exist, both study sites and CROs should be consulted for recommendations on which IRB to engage with. Given their independent nature, they can have vastly different timelines and be more conservative/progressive despite covering the same participant population and intervention. DSMBs are best staffed with senior experts in the field, e.g. from medical societies, academic publications, or from the personal network. Connect through professional bodies, educational institutes, or their official online avenues.

• Public engagement and non-profits: Engage in community events, visit the organisations’ websites, or even go to their social media. 

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Other articles in this series

1. Stakeholders in Drug Development
2. The Blueprint of Drug Development
3. Origins of Drug Regulation
4. Recommended Literature and Courses
5. Alvea – A Case Study of the Fastest Biotech to Go to In-Human Trials
6. Conclusions