Practical Pointers for Drug Development and Medical Affairs / May 2023

Written by Gerald L. Klein, MD & Roger Morgan, MD

Drug Development

  • Informed consents have grown much larger, more complex, and oftentimes uses terminology that may be difficult to understand for persons with limited language skills. [1] It is imperative to make these forms shorter, simpler, and easier to understand. Studies have demonstrated poor patient comprehension of the essential elements of the informed consent process not just in the United States but globally. [2] [3] [4]

  • The definition of a laboratory adverse event is usually described in the protocol as a value that is clinically significant in the investigator’s judgment. One frequent protocol guidance for this is having a lab test reported as clinically significant if repeated. However, many results are repeated just to ensure that the results are insignificant or are due to a procedural error (hemolyzed blood). We recommend removing “repeat laboratory testing” as an indicator of a significant adverse event.

  • Removing all patient identification is important for sites to remember when they send patient hospital records or other medical records to the sponsor or CRO. In addition to name, it also includes items such as home address, telephone number and medical record number.

    Medical Affairs

  • Making the most out of poster presentations

    • Place on social media

    • Solicit comments and questions

      • Answer appropriate questions and communicate these to a wider audience

      • Broadcast current and future work in this area when applicable

    • Write up and disseminate pertinent questions and answers

    • Create a white paper and journal articles from the data

  • Commercial booths at scientific conferences

    • Verify that a promotional committee consisting of legal, medical, and regulatory (LMR) has reviewed your booth and all material in detail. This includes the following:

      • Booth location

      • All banners

      • All printed material, videos, handouts, etc.

      • Labels, headers, designs, etc. on the booth wall

      • Location of medical science liaisons (MSLs) in relation to the commercial team

    • Detailed examination of all items is critical to maintain compliance with the regulations.

  • Product feedback is an important way to learn how health care providers are actually using your product

    • Having MSLs talk directly to clinicians is a way to gather this information. In addition, you can learn why and when they are actually using the product in this manner.

    • What difficulties or drawbacks are there to the product?

    • Can the patient experience be improved, such as administering a drug at bedtime?


      [1] Schumacher A, Sikov WM, Quesenberry MI, Safran H, Khurshid H, Mitchell KM, Olszewski AJ. Informed consent in oncology clinical trials: A Brown University Oncology Research Group prospective cross-sectional pilot study. PLoS One. 2017 Feb 24;12(2): e0172957. doi:10.1371/journal

      [2] Ibid

      [3] O'Sullivan L, Sukumar P, Crowley R, et al. Readability and understandability of clinical research patient information leaflets and consent forms in Ireland and the UK: a retrospective quantitative analysis. BMJ Open 2020;10: e037994. doi:10.1136/bmjopen-2020-037994

      [4] Wen G, Liu X, Huang L, Shu J, Xu N, Chen R, et al. (2016) Readability and Content Assessment of Informed Consent Forms for Phase II-IV Clinical Trials in China. PLoS ONE 11(10): e0164251. https://doi.org/10.1371/journal.pone.0164251

       

 

Practical Pointers for Drug Development and Medical Affairs

Written by Gerald L. Klein, MD & Roger Morgan, MD

Drug Development

  • Up to 50% of subjects have poor medication adherence in clinical trials. This can be a significant factor affecting the efficacy of the results. In order to prevent this, it may be worthwhile to do a placebo screening for 2-4 weeks to determine if the potential participant will demonstrate adequate medication adherence to be enrolled in the study.1

  • The constant change of regulations, introduction of new technology and the modifications of best clinical trial practices, makes the need for continuing staff education and training essential. This type of guidance will help maintain the highest clinical practice standard for your company and may also prevent staff turnover.

  • The signing of an Informed Consent Form is not totally adequate in obtaining a potential participants informed consent for a pharmaceutical clinical trial. The process should also involve a careful, meaningful explanation of potential risks and a commitment to attend all required patient visits and procedures. These procedures should be clearly defined so that the potential subject understands their actual commitment. This is not only a regulatory requirement but an ethical, moral, and medical obligation. If potential study participants better understand the risks and their obligations it should also aid with patient retention.3

    Medical Affairs

  • A practical method to demonstrate the application of a biopharmaceutical product may be to publish a case history or series about this topic. Through these articles, health care providers are able to identify the example with their own patients and how this product may fit in with their practice.4

  • The use of n-1 clinical studies is another cost-effective manner of conducting small pilot clinical studies.5 They are especially useful in patient-centric research and to re-evaluate chronic therapies.6

  • Medical Affairs teams frequently want to work with established experts, Key Opinion Leaders (KOLs), in specific therapeutic areas.7 These teams should have an ethical synergistic plan that provides benefits for both the clinical scientist’s research and/or patient care (as well as addressing their own needs) allowing for a prudent exchange of ideas. Rather than compensating a physician only for their time, a more useful activity will help establish a better relationship. An example is a medical liaison (working for a company that sells allergy products), contacting a prominent allergist to determine what pollens seem to cause nocturnal allergy symptoms in July in San Diego.

  1. Klein GL. The case for digital pill use in clinical trials. Clin Trial Pract Open J. 2021; 1(1): 89-94

  2. Butryn, Tracy, et al. “Keys to success in clinical trials: A practical review.” International Journal of Academic Medicine 2.2 (2016): 203.

  3. Yarborough, M. Rescuing Informed Consent: How the new “Key Information” and “Reasonable Person” Provisions in the Revised U.S. Common Rule open door to long Overdue Informed Consent Disclosure Improvements and why we need to walk Through that door. Sci Eng Ethics 26, 1423-1443 (2020).

  4. Riley, David s., et al. “CARE guidelines for case reports: explanation and elaboration document.” Journal of clinical epidemiology 89 (2017) 218-235.

  5. Duan N, Kravitz RL, Schmid CH. Single-patient (n-of-1) trials: a pragmatic clinical decision methodology for patient-centered comparative effectiveness research. J Clin Epidemiol. 2013 Aug;66(8Suppl):S21-8

  6. Vohra, S., Shamseer, L., Sampson, M., Bukutu, C., Schmid, C.H., Tate, R., …& Moher, D. (2015). CONSORT extension for reporting N-of-1 trials (CENT) 2015 Statement. bmj, 350.

  7. Scher, J.U., Schett, G. Key opion leaders - a critical perspective. Nat Rev Rheumato/17, 119-124 (2021).

Potential Errors and Corrections in Early Phase Drug Development

Clinical Trials and Practice / Open Journal

by Gerald L. Klein, MD and Roger Morgan, MD

ABSTRACT: Many foreign and small companies trying to enter the United States biopharmaceutical market make avoidable errors in their early clinical phase drug development and clinical trials. They need to first understand the risks that they must endure with patent law, regulatory hurdles, the complexity and duration of the necessary clinical trials, and the large cost of drug development, which often necessitates raising substantial capital from investors. If appropriate capital for these clinical studies must be raised, then the company must be able to clearly articulate a realistic expected return on investment to these individuals. So, they must also understand the market, its exclusivity, and the competition. This must all be put together in a sleek pitch deck. Early errors frequently begin with too few, inadequate, or poorly constructed patents. These and other risks and errors may be prevented by the use of an experienced product development team. Many of these errors could be avoided if companies used more experienced drug development professionals to assist them in selecting the optimum patent strategy, regulatory plan, budget, contract research organization (CRO), clinical investigators, and etc. It is hoped that this opinion piece will help make early clinical trials more effective and save time and money.

Read Full Article

The Case for Digital Pill Use in Clinical Trials

Clinical Trials and Practice - Open Tournal (CTPOJ)

by Gerald L. Klein, MD / Published August 17, 2021

Abstract: Medication adherence in clinical trials is significantly overestimated through every phase of drug development. This can cause a reduction in statistical power, potentially resulting in incorrect conclusions regarding efficacy, safety, tolerability, and dose-response relationships, in addition to major cost overruns. Digital pill systems enable adherence measurement through an embedded ingestible sensor paired with an external receiver. An oral pharmaceutical product is over-encapsulated by a pharmaceutical-grade shell containing a biocompatible sensor. Upon exposure to gastrointestinal fluid, the shell dissolves and the sensor is activated. Medication ingestion data is transmitted via a digital signal. Clinicians and researchers use this data to track, in real time, when and if a medication was taken. These systems have demonstrated a 99.4% rate of accuracy, and have over 15-years of supporting experience and safety data. Spurred by the accelerated adoption of technology in healthcare and in everyday life, patients have become tech-savvy. They quickly adapt to these devices, and are able to use them safely and effectively. Digital pills can be implemented in most types of studies. In early-stage trials such as pharmacokinetic and pharmacodynamic studies, or dose-finding studies, accurate information on maximum-tolerated dose levels is essential and cannot be established unless study participants are highly adherent. In later-stage pivotal trials, effective medication adherence tracking can strengthen the dataset and confidence in the study results. Significant nonadherence may generate results that do not meet statistical or clinical significance for the critical endpoints, resulting in at worst, a failed trial, or at best, the need to enroll additional patients at substantial additional cost. Most clinical trials fail to achieve statistical significance, and poor medication adherence is often an important contributor. A digital pill system can ensure the quality and integrity of adherence data, increase confidence in the overall study data, and improve clinical trial efficiency.

Full article available here


The Importance of Teaching and Fostering Clinical Research in Primary Health care

Gerald L. Klein, MD and Mark A. Brown, PhD

It is important for primary health care (PHC) teaching institutions and hospitals to create an atmosphere fostering clinical investigation for all health care practitioners (HCP). This involves not just clinical trials, but observations, examinations, and investigations are a critical part of the education of any health science students. This is the basis of science. Without knowing how to apply a scientific thought process and methodology to a clinical situation, it will prevent one from reaching their optimum abilities. Continue reading…


Recognizing High Risk Traumatic Wounds and Preventing Infections and Complications

Review Article / Emergency Medicine and Trauma Care Journal

by Gerry L. Klein and Peter C. Johnson, MedSurgPI, LLC

Abstract: Simple traumatic wounds are a frequent event that can usually be managed without sequelae, unless the wound is of high risk. High risk wounds have a greater propensity to become infected and complicated. Such wounds are characterized by a specific type of wound (i.e. jagged), location of the wound (i.e. lower leg); and patient’s underlying medical condition (i.e: diabetes).If these wounds become infected, they have a negative impact on morbidity, mortality, quality of life, and costs. The take-away should be a wake-up call to physicians specifically and healthcare professionals more broadly that a much more aggressive and effective treatment regimen to prevent wounds from becoming infected is required. Such a regimen should likely include a comprehensive understanding of wound types, the degrees of microbial contamination, and novel ways to prevent infections through wound debridement and irrigation.

Link to read the entire article

Dr. Gerry Klein to serve as panelist on Webinar: Wound Infection in Humanitarian Emergencies

group picture on wound infection Humanitrian Emergencies.jfif

 #PrepareToProtect #IRPWebinar #MedicalResponse #HumanitarianEmergencies #GFARC #WHO  

 We at MedSurgPI, LLC are delighted to participate in and invite you to a webinar on wound infection, organized by Infection Reduction Partners, an initiative to promote and champion cross-sector collaboration and partnerships towards the effective reduction of infection rates worldwide. 

 This webinar will explore the cross-sector data, guidelines, and best practices in wound infection during disaster response and humanitarian emergencies. A presentation of practical and innovative options to reduce the risk of infection will be shared and we will discuss current publications including IFRC’s “International First Aid, Resuscitation and Education Guidelines 2020,” WHO’s Guidance, “Prevention and Management of Wound Infection,” WHO/ICRC’s “Management of Limb Injuries,” and WHO’s “Global Guidelines for the Prevention of Surgical Site Infection”.

 Panelists: 

- Dr. Pascal Cassan, MD, Head of Global First Aid Reference Centre, International Federation of Red Cross and Red Crescent Societies
- Flavio Salio, Team Lead - Emergency Medical Teams at the World Health Organization
- Kim Delahanty, BSN, PHN, MBA/HCM, CIC, FAPIC, Infection Prevention Control Advisor/Referent, Médecins Sans Frontieres USA/OCP (Doctors without borders)
- Dr. Gerald L. Klein, MD, Principal at MedSurgPI, LLC, wound infection consultant 

Moderator: 

Tessy Antony de Nassau, Ambassador for UNAIDS, and Patron to UNA-UK

 Find out more on IRP social media Facebook, YouTube, Twitter, Instagram, LinkedIn!   

Audience: 

  • Medical team members involved in humanitarian aid, disaster relief, and emergency response: Medical directors, doctors, nurses, technicians, responders, infection preventionists, health officers, medical team leaders

  • NGOs

  • International Organizations

  • Government/Ministries of Health

The Medical Monitor is one of the key players in keeping subjects safe in clinical trials. This article helps explore the role of the Medical Monitor

Journal of Clinical Research Best Practices

Medical Monitoring of Clinical Research Studies

By Gerald L. Klein, Peter C. Johnson, and Roger Morgan

Introduction

The Medical monitor’s (MM’s) primary responsibilities in a clinical trial are to oversee the safety and protection of the research subjects and to provide independent oversight to help ensure the scientific reliability, clinical integrity, and quality of the clinical trial. Although the Food and Drug Administration (FDA) has not spelled out the necessity and role of the medical monitor, MM participation is important for compliance with Good Clinical Practice (GCP) guidelines and MMs almost always play a significant role in multicenter clinical trials.1 The best practices for MMs described in this article can also help study sponsors comply with International Council for Harmonization (ICH) guidelines, Technical Requirements for Pharmaceuticals for Human Use, the United States Code of Federal Regulations (CFR), and FDA regulations and guidances.2

The MM collaborates with the project manager, safety, data management, biostatistics and quality departments, principal and sub-investigators, the site coordinator, the Data & Safety Monitoring Board (DSMB), and any other group that directly or indirectly protects the safety of study participants.

Communications

Prompt and transparent communication is an essential element underlying safety in all human clinical studies.3 The MM should be the point person for medical, scientific and safety questions posed by clinical investigators, their site personnel, and staff at the study sponsor and contract research organization (CRO) involved in the trial. The MM’s contact information should be readily available to investigators and their staff. The MM should be available essentially 24/7 with a back-up MM when the primary MM is not available.

MMs often address significant questions on the following topics:

  • Documentation

  • Protocol and investigator brochure

  • Inclusion criteria

  • Exclusion criteria

  • Safety

  • Patient concerns

  • Adverse events (AEs)

  • Serious adverse events (SAEs)

  • Suspected Unexpected Serious Adverse Reactions (SUSAR)

  • Pregnancy

  • Medication errors

  • Concomitant medications

  • Laboratory values

  • Protocol deviations and waivers

  • Informed consent

  • Unblinding

  • Early termination or withdraw of a subject

  • Protocol-stopping rules

  • Other topics related to clinical research

  • DSMB and pharmacovigilance team questions with respect to adverse events

MMs document all relevant communications in the appropriate database. When there are multiple significant errors at an investigational site, the MM may be called into an investigation to determine the cause and whether corrective actions or new training is required.4 In rare cases, the MM, together with the project manager and quality assurance, assesses whether a site must be removed from a study due to safety issues, poor data quality, or violation of GCPs.

Maintain a Question and Answer (Q & A) log. Create anticipated Q & A’s prior to the study and then maintain a log to help provide quick, accurate and consistent answers to repeat questions. The clinical sites should be able to search the log for themselves.

Protocol and Investigator’s Brochure (IB)

The MM may write all or just parts of the protocol and investigator’s brochure. At minimum, the MM should review and approve these documents.5 Since the MM is expert on the protocol and the specific therapeutic indication being studied, the best practice is to involve the MM in training sponsor and/or CRO staff as well as the investigators and their personnel on the protocol and IB.

The MM should ensure that protocol endpoints make medical and scientific sense and are safely achievable. The clinical trial’s expected benefits must outweigh its risks.6 Inclusion and exclusion (I/E) criteria must align with this goal. I/E criteria must prevent the enrollment of subjects who are unlikely to obtain a positive therapeutic clinical endpoint or would be put at unacceptable risk in the study. For instance, a patient with a childhood history of bronchial asthma may not be appropriate to enroll in a clinical trial testing a medication that has properties of beta blockers, which can exacerbate symptoms of asthma.

The MM reviews permitted and prohibited concomitant medications (including over-the- counter drugs, herbs and dietary supplements) for possible interactions with the molecule being studied. The MM also ensures that the protocol does not specify types or numbers of procedures that would pose unnecessary risks for study subjects. The MM may recommend ways mitigate such risks.

The MM ensures that the IB clearly describes non-clinical studies and any adverse events of special interest (AESIs). An example of an AESI would be an abnormal electrocardiogram when all cardiac adverse events are of special interest to the regulatory authorities. All current knowledge about the drug, device or biologic must be clearly spelled out in the IB, not hidden in esoteric study reports.7 It is unfortunate that many investigators do not read the IB in detail. Therefore, the MM should try to convey the important aspects of the pharmacokinetics, pharmacodynamics, metabolism, drug interactions and expected adverse events associated with the study therapy to the investigator and the appropriate staff at the clinical site.

Review and Discussion

The MM reviews each subject’s eligibility data, screening physical examination results, medical history, concomitant medications, and laboratory tests before approving their entry into the study. If the investigator is attempting to enroll unqualified subjects, training may be required. The MM thoroughly discusses non-trivial protocol deviations (PDs), which should be rare, with the investigator, and only the most minor ones should be approved. A major PD may affect subject safety, data integrity, or the integrity of the entire study.8 A dosing error by which a subject received twice the dose of the investigational drug during one dosing interval would be a major deviation. A subject’s labs being a few hours out of the visit window would be a trivial deviation.

If time permits, the investigator should consult with the MM before unblinding a subject so the MM can assess and document the decision. The investigator should also discuss with the MM any early unusual termination or withdrawal of a subject from the study.

Data & Safety Monitoring Board (DSMB) or Data Safety Committee (DSC)

If there is a DSMB or DSC, the MM should participate in the blinded section of any meetings to help answer any questions related to adverse events and other potential safety and enrollment issues.9

Adverse Events

One of the most significant MM responsibilities is to work with the investigator to determine the most accurate causality of Serious Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions (SUSARs). SUSAR expectedness determinations should be based on the Reference Safety Information section of the IB, or, in studies of marketed drugs, the applicable package insert. Many investigators do not have a good understanding of causality assessment, and poorly defined regulatory terms and examples do not help the situation.10 Following the CIOMS report recommending a binary approach of “related” or “not related” in determining causality simplifies the complex and confusing terminology.11 There is no accepted standard for assigning causality to an SAE, but employing the following Bradford Hill Criteria is an excellent way to determine causality:12,13

1.       Strength of Association. A strong association between a treatment and an adverse event indicates causation. For example, each time the drug was given to a subject, it caused vomiting within a predictable time period.

2.       Consistency. Established adverse event attributions or previous determinations in similar situations indicate causation.

3.       Specificity. An established mechanism of action connecting the treatment and the adverse event indicates causation.

4.       Temporality. Exposure to the product must occur before the disease or event, and not after a latency period. However, temporality is not sufficient to establish causation.

5.       Biological Gradient. A dose response effect is a strong argument for causation.

6.       Plausibility. The causal relationship is biologically plausible.

7.       Coherence. The known facts fit the natural history and biology of the disease.

8.       Experiment. Epidemiologic studies indicate causation.

9.       Analogy. A similar agent causes the same type of AE.

 Safety and Pharmacovigilance Reporting

The MM develops or reviews a brief narrative describing each SAE and SUSAR, which should include the following elements:14

  • Clinical event (postmortem findings if applicable)

  • Course of event, with temporal relationship to experimental product

  • Outcome of the event with the nature, severity and intensity

  • Relationship of the subject’s medical history and concomitant medications to the event

  • Significant test results or laboratory findings

  • Therapeutic treatment for the event

  • Action, if any, taken with regard to experimental product

  • Causality assessment by investigator and sponsor

  • Review and analysis of similar events with the experimental product

The MM works with the safety/pharmacovigilance team to code adverse events based on the latest edition of the Medical Dictionary for Pharmaceuticals for Human Use (MedDRA).15 The MM also reviews the coding of concomitant medications using the World Health Organization’s (WHO’s) latest edition of pharmaceutical names (when it is used in the clinical trial). The MM reviews all SAE and SUSAR reports for accuracy and completeness and is the point person to discuss such events with the sites.

 Conclusion

Since there are no regulatory guidelines on MM duties, this article has discussed those that are most significant. With the possible exception of the lead principal investigator, the MM should be the person most expert on the medical and scientific aspects of a multicenter study. The principal investigator at each site and the MM, along with DSMB and the institutional review board (IRB), share primary responsibility for the health and safety of study subjects and ensure the validity of the study. They must establish working relationships to ensure that subjects are protected and study data, including SAE and SUSAR reports, are accurate. This profound responsibility means that the MM for a study must have the requisite expertise, personality, dedication and ability to use the processes outlined in this article.

 References

  1. Vijayananthan A. et al., “The importance of Good Clinical Practice guidelines and its role in clinical trials.” Biomed Imaging and Intervention Journal, 2008; 1: e5.

  2. E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6 (R1) Guidance for Industry, FDA, March 2018.

  3. “FDA Guidance for clinical investigators, sponsors, and IRBS: adverse event reports to IRBs-Improving human subject protection,” FDA, Jan 2009.

  4. Knepper D. et al., ‘Detecting data quality issues in clinical trials: current practices and recommendations,’ Therapeutic Innovation 7 Regulatory Science, 2016; 50:15- 21.

  5. World Health Organization, Guide for writing a Research Protocol for research involving human participation; 2014.

  6. Emanuel E. et al., “What makes clinical research ethical?” JAMA, 2000; 283:2701- 2711.

  7. Fiebig D. et al., “The investigator’s brochure: A multidisciplinary document,” Medical Writing, 2014; 23:96-100

  8. Attachment C: Recommendation on Protocol Deviations, Office of Human Research Protection, HHS.gov.

  9. Calis A. et al., “Understanding the functions and operations of data monitoring committees: survey and focus group findings,” Clinical Trials, 2017:59-66.

  10. Morse M. et al., “Monitoring and ensuring safety during clinical trials,” JAMA. 2001; 285:1201-1205

  11. “Management of Safety Information for clinical trials: Report of CIOMS VI,” 2005.

  12. Federak, K. et al., “Applying the Bradford Hill criteria in 21st century data integration has changed causal inference in molecular epidemiology.,” Emerging Themes in Epidemiology, 2015; 12:14-23

  13. Howick, J., “The evolution of evidence hierarchy: What can Bradford Hill’s guidelines of causation contribute?” Journal for the Royal Society of Medicine, 2009; 102; 2009:186-194

  14. Modified from Ledade, S. et al., “Narrative writing: Effective ways and best practices. Perspectives in Clinical Research,” Perspectives in Clinical Research, 2017; 8:58-62

  15. Brown. E. G., “Using MedDRA: implications for risk management,” Drug Safety. 2004;27(8):591-602

Authors

Gerald L. Klein, MD, is a principal at MedSurgPI. Contact him at 1.919.930.9180 or gklein@medsurgpi.com.

Peter C. Johnson, MD, is president and CEO of Cell X Technologies.

Roger Morgan, MD, is vice president of medical affairs at MedSurgPI, LLC.

Improving Clinical Trial Safety

There is a dire need to establish transparent medication safety guidelines and to assure the public of the industry’s commitment to this task.  Clinical investigators and their staffs who conduct clinical trials often do not understand some of the regulatory methodology used to assess medication safety, particularly with regard to the assignment of causality to drug-related Serious Adverse Events.  Yet, this is critical to establish the safety of medication.   The medical monitor in a clinical trial can help educate and guide investigators in a clinical study with regard to accepted causation assignment.  Since there is a paucity in the literature regarding medical monitoring of clinical trials, this article will help to fill this gap, and to provide a guide to establishing proper causality of an adverse event.  This open access article can be found at Medical Monitoring of Clinical Research Studies.