How To Rescue Your Clinical Trial When at Risk to Fail | Heike Schön on Beginner’s Mind with Christian Soschner

Key Takeaways

  • According to Heike Schön, the earlier you start a clinical trial, the better
    • You need to streamline your pre-clinical results with your plan of clinical trials (your synopsis, target product profile, etc.)
  • The sponsor is the company providing the financing and the organization for the compounds of clinical trials. They are not necessarily the investors
    • The drug development process is operating in a highly regulated environment and sponsors have a lot of duties when a company conducts a clinical trial
    • Sponsors have the final responsibility
  • FDA and EMA publish inspection reports, which can be beneficial to check out to learn what to avoid
  • When to Start Preparing a Clinical Trial?
    • A minimum is one year, but the more the better
  • Lumis’ rule of thumb: when you outsource a clinical trial, for every five to seven people working in a Contract Research Organization (CRO) on your clinical trial, you should have one person in your company conducting oversight
    • “The oversight should provide you with a clear picture of where your clinical trial stand and with alerts if something goes wrong.”Heike Schön 
  • The majority of clinical trials fail because they fail in enrollment timelines
    • When you are recruiting sites, really look at what kind of patients they have and if they fit in your protocol
  • When a clinical trial goes wrong do a very good root cause analysis
    • The part that often goes wrong is feasibility assessment (e.g. enrollment and miscalculation of the environment)
  • Relationship between the sponsor and investor – investors should be much more involved in overseeing their investment and working with the sponsors
    • Real-time understanding of what’s going on with your clinical trial, e.g. many of the CROs nowadays have study startup managers
  • There will be much more individualized medicine available in the future due to technology 
    • Decentralized clinical trials (future possibility)- get drugs to market more quickly and at less cost
    • The digital twin concept- can be used for comparable data and reduce the number of patients enrolled in clinical studies

Intro

  • Heike Schön (@LumisIntl) is the co-founder and managing director of Lumis International. She has worked in management positions in clinical research for more than 20 years
  • 90% of all product ideas fail in clinical trials. Heike Schön joins Christian Soschner to talk about why clinical trials fail and how to reduce the risk of failure, steps to getting your clinical trial back on track, and the future trends of clinical trials
  • Host Christian Soschner (@Soschner)

Introducing Lumis International

  • Lumis International are helping global biopharmaceutical and medical device companies access the European market more quickly, efficiently and cost-effectively
    • They were founded in 2013 to support small to midsize companies as their legal representative when running clinical trials in Europe
    • To conduct a clinical trial in Europe as an outside company, you have to have a legal representative
  • In 2020, Lumis Life Science Consulting was founded as a subsidiary company of Lumis International with the focus to provide consulting and solutions

When Is the Right Time to Start a Clinical Trial?

  • According to Schön, the earlier you start a clinical trial, the better
  • First, you must have a business plan (which always includes clinical research and clinical activities)
    • You need to streamline your pre-clinical results with your plan of clinical trials (your synopsis, target product profile, etc.)
    • Your pre-clinical data and your plan of clinical trials always need to match, otherwise, you get into problems with regulatory approvals
  • “Clinical trials are part of the way to the market and implementing them early on helps in planning the business.”Christian Soschner

Sponsor’s Role and Importance

  • The sponsor is the company providing the financing and the organization for the compounds of clinical trials
    • It’s not the job of the CRO 
    • Sponsors are not necessarily investors
    • The sponsor company defines the plan, the drug, the main responsible party
  • The drug development process is operating in a highly regulated environment and sponsors have a lot of duties when a company conducts a clinical trial
    • The final responsibility is always with the sponsor
  • ICH: E 6 (R2) document clearly define the roles of a sponsor
  • As a sponsor, you have to: 
    • Oversee the clinical trial 
    • Prove that you oversee the clinical trial
    • Have the finances when you start the trial (go for a part contract if you don’t have enough money)
  • Quality management is a big issue because of safety concerns 
    • Sponsors have to ensure their quality management systems are in place for the whole process of drug development
    • They have to do it to guarantee the safety of the patients, but also to be ready for inspection
  • The inspection might not come in the first human study (latest in phase 2), but you have to be ready 
    • They will examine all the details of your oversight, planning, vendor selection, vendor validation, how did you qualify your vendors, etc.
    • FDA and EMA publish inspection reports, which can be beneficial to check out to learn what to avoid
  • Inspection reports always lead to changes and adaptations of regulations (one of the reasons why ICH was revised)
    • When you have an inspection in e.g. phase 3, inspectors go to the sponsor, to the CRO, and the sites

When to Start Preparing a Clinical Trial?

  • Consider what takes the longest time to be developed 
    • It’s probably going to be the investigation of the drug
    • Depending on the ingredients, drug investigation could take up to 1 year
  • It all depends on the company
    • Some companies do CRO selection on short notice, and others do it before the study starts
    • “I would always allow for much more time to prepare and to discuss in detail the plan of the clinical study with the regulatory researchers.”Heike Schön
  • A minimum is one year, but the more the better

Producing a Proper Financing Option

  • The clinical trial doesn’t need to be entirely financed before filing with the authorities, but it is recommended
    • It’s not always possible. If you foresee having issues with the financing, try opting for a contract that only covers one part of the process (e.g. just the study startup)
    • It’s better than running out of capital in the mid of the clinical trial process
  • Be careful with the financing process; awareness about what is needed until the end

In-House Vs Outsourced Clinical Study Management

  • For example, if the CRO is conducting your clinical trial, you have to make oversight management of the different activities
    • You should have experience people (medical person or project manager) who can conduct the oversight with awareness of what can happen and how to mitigate the risks
    • It’s a classic risk management approach
    • It’s not a job only for a clinical trial assistant; they can’t cover all the activities even if they are very good at their job
  • Lumis’ rule of thumb: when you outsource a clinical trial, for every five to seven people working in a CRO on your clinical trial, you should have one person in your company conducting oversight
  • What should proper oversight management look like?
    • It depends on the CRO you are working with
    • Good key performance indicators (KPIs) are a must 
    • 7-10 well-chosen key performance indicators
  • You have to know what is happening in your clinical trial, as real as possible
    • What is impacting the timelines, the costs, the safety
    • These key performance indicators can be developed together with the CRO (they have the data management and the study startup system)
    • You define it together and get regular reports on the key performance indicators
    • You don’t need to do this by yourself; the problem a lot of sponsors have
      • They do micromanage the CRO and they double their work
  • “The oversight should provide you with a clear picture of where your clinical trial stand and with alerts if something goes wrong.”Heike Schön 

Three-Step Checklist for Sponsors to Keep Studies on Track

  • It’s all about communication, motivation, and clear management
    • Establish very clear and transparent communication with the vendors 
    • Clearly developed roads and responsibilities – a sponsor should very clearly communicate their expectations at the beginning to the vendors
    • Try to develop good business intelligence (dashboard), KPIs in place and work with them for study performance

Failing in Enrollment Timelines

  • The majority of clinical trials fail because they fail in enrollment timelines
    • Selection of the sites: “Do you have the right sites ready for you to start working, are they ready for you to start working, is the CRO ready and initiating the sites immediately after you get a positive approval from the authorities?”- Heike Schön 
  • Study startup and preparation time are key activities for your clinical trial
    • Enrollment can lag behind your timelines; sites may have only one or two patients that fit your protocol
    • When you are recruiting sites, really look at what kind of patients they have and if they fit in your protocol
  • A deeper look at study requirement rescue for enrollment
    • When a clinical trial goes wrong you should do a very good root cause analysis
    • The part that often goes wrong is feasibility assessment (e.g. enrollment and miscalculation of the environment)
  • The key to a startup is a proper feasibility assessment for a clinical study
    • It’s normally done by CROs because they are familiar with the sites, the countries, the incidences of the diseases, etc.
    • Don’t save money on this. The use of the feasibility results is very often underestimated

The Fine Line Between Micromanaging and Managing Relationships

  • “Managing expectations is the key to the success of the clinical trial.”Heike Schön 
  • Relationship between the sponsor and investor – investors should be much more involved in overseeing their investment and working with the sponsors
    • Real-time understanding of what’s going on with your clinical trial, e.g. many of the CROs nowadays have study startup managers (different from project managers after patient enrollment starts)
    • They do all the proper planning during the clinical trial application, initiation of the next site, when can the first patient be enrolled, etc.
    • These are critical numbers that need to be tracked very closely
  • Sponsors should always be involved in this part and know when the study and site are initiated, when does the site start, etc.
    • A lot of the small sponsors think they don’t have to be involved because nobody knows them, but that’s exactly the reason why they should be involved
    • “Active management should not be underestimated.” Christian Soschner
  • Many study sites do many studies in parallel so managing your relationship with them could also be beneficial (stay in touch), it’s always good to maintain and build relationships
    • Maintain contacts; you have video calls if COVID is stopping you

It’s All About Communication and Mediation

  • “A clinical trial is dealing with human beings, it’s is not a machine to just flip the switch and then it runs for two years and produces a study report.”Christian Soschner
    • Once again, a proper root cause analysis is a must
  • When Lumis get involved as a mediator, they always try to be neutral
    • They avoid blaming anyone in particular (project manager, sponsor, CRO, etc.) and try to really understand what went wrong in the process
    • If bad communication is a problem, they optimize cooperation between sponsors and CRO
  • The company’s senior management must get involved, and the CEOs
    • There are different layers of communication: day-to-day work with project managers, but there is also the “C-level”, the company owners need to talk and agree on how to improve communication
    • They should be critical of themselves; should the protocol be changed? Should they get better patients, add countries?

Root Cause Analysis Process

  • Once again, it’s all about dealing with human beings, a huge management function
    • They look at the different processes that were established at the companies
    • What did the sponsor establish to select a CRO to perform oversight, to manage the study?
    • They look at the process in detail with different specialists; a quality manager, an IT specialist if there is a lot of technology involved
  • Bringing the teams together to get all the perspectives and think about what could have been done differently (joint solutions)

Avoiding Point of No Return With the Clinical Trial

  • It’s almost always a leadership problem and team building problem 
    • Get involved from the beginning and have real-time data on where the clinical trial stands
  • It’s important to know your contact persons on all the different levels
    • Keep emotions out of the decision-making process and motivate people to speak up and look through the problems to the root causes
    • Heike Schön always recommends preparing a governance chart so everybody knows who to talk to in which cases
  • Have escalation procedures
    • Sure, everything can work well but you always have to be prepared for the worst-case scenario; that’s why there are contracts
    • With a contract, you already define certain activities, e.g. milestones, enrollment of patients, etc.
  • For team building:
    • Team building exercises during a kickoff meeting
    • Have a team vision; how to work together
    • When interpersonal problems occur, look back on the team vision, be solution-oriented and respectful in communication

Evolution of Clinical Trials and Drug Development in the Last Few Decades

  • The focus is more on personalized/precision medicine
    • There will be much more individualized medicine available in the future due to technology 
  • Does that mean more complexity for future clinical trial planning?
    • Not really, according to Schön. The data used for feasibility assessment will be available upfront (especially for rare diseases)
  • COVID’s positive outcome on technology:
    • Technology was more accepted, also by the regulatory authorities, they easily adjusted
    • Patients couldn’t come to the hospital anymore which lead to decentralized clinical trials (telemedicine, online interviewing, study nurses)
    • Usually, patients were demotivated when spending a lot of time on the sites and confronting the logistic problems
  • Hybrid future possibility- maybe patients won’t always have to go to sites to be part of the trial
    • Also, the use of electronic informed consent in some countries
  • Decentralized clinical trials (future possibility) get drugs to market more quickly and at less cost
    • The digital twin concept- can be used for comparable data and reduce the number of patients enrolled in clinical studies
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