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

Drug Development

• It is often difficult to locate academic clinical research sites that are not already filled to capacity or who are so short-staffed that they cannot take on new projects.  This provides an opportunity to work with and help educate and train the lesser-known medical institutions that have both the medical expertise and specific patients but lack substantive experience in clinical trials. 

• Currently, there is a greater emphasis on enrolling additional populations that have not adequately participated in clinical trials such as minority, geriatric, and pediatric populations.  Investigators should ensure that these potential subjects fully understand the risks and benefits (the informed consent process) of participating in these studies. It. may be useful to have them answer a series of standardized questions to demonstrate that they understand the essential elements of the Informed Consent Form (ICF) (IRB approval should be obtained for the questions if in written form).

• The following are links to FDA webpages and documents relating to the pre-IND and IND process that should be reviewed when developing your pre-IND submission briefing package:

• Small Business and Industry Assistance: Frequently Asked Questions on the Pre-Investigational New Drug (IND) Meeting

• Investigational New Drug (IND) Application

• Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators

• Guidance for Industry: Content and Format of INDs for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products

Medical Affairs

• New AI tools, ChatGPT for example, may be helpful in writing journal articles. This is especially true for providing an outline of the topics that you want to cover in the article.  It may also be useful in finding references to help produce your original material, but they should be checked for accuracy. 

• When launching a new product or introducing a new indication of an established product, we recommend that you have multiple review articles discussing your product from not only an efficacy and safety standpoint, but also from a pharmacoeconomic standpoint and potential position in the Health Care Provider (HCP) therapeutic regimen. 

• When promoting your product, you may want to emphasize the importance of the individual patient reaction to a specific medication.  Just because they reacted poorly or insufficiently to one drug in a specific class, does not mean they will react the same way to all drugs within that class.[1]

[1] Sundström J, Lind L, Nowrouzi S, et al. Heterogeneity in Blood Pressure Response to 4 Antihypertensive Drugs: A Randomized Clinical Trial. JAMA. 2023;329(14):1160–1169. doi:10.1001/jama.2023.3322

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).

Practical Pointers for Drug Development and Medical Affairs / January 31, 2023

Drug Development

• It is absolutely an essential part of the clinical research process in providing Informed Consent, and having the potential participant sign the forms (ICF).1 It may help foster enrollment by also explaining to potential study participants not only why the research is being conducted, but also how their individual participation will help in product development and what this product has the potential to accomplish.

• It is more difficult than ever to enroll patients in Phase I oncology clinical trials.2 One partial solution, when feasible, is to make this a multi-center semi-decentralized clinical trial rather than one inhouse unit.

  • Making some of these visits home visits may further enhance enrollment.

  • This will open up a wider enrollment area.

  • This may decrease subject travel time and costs.

• The FDA will now start in-person meetings.

  • This gives companies the ability to have face-to-face dialogue with the agency.

  • Such meetings may provide a better chance for companies to present their data and reasoning.

  • Proper preparation with an experienced team is critical to success at these meetings.

Medical Affairs

• Writing medical case studies is an excellent method to demonstrate your products’ attributes in an actual clinical example. It shows clinicians the practical aspects of the diagnostic or therapeutic intervention.3

• According to Erica Dankiewicz, “The promotional review committee is a multi-disciplinary group with representatives from Medical, Legal and Regulatory and is often referred to as MLR.” Together, as a team, they ensure materials are fair balanced and meet function-specific standards while achieving marketing’s goals. In the US, the Federal Food, Drug, and Cosmetic Act (FD&CA) and Title 21 of the Code of Federal Regulations (CFR) predominantly govern prescription drug advertising and promotion”4 When conducting Legal, Medical, Regulatory Review, it is important to be conservative and follow the exact wording of the package insert.

• Clinicians frequently come up with new potential uses for approved products. Allowing these physicians to conduct an investigator-initiated trial (IIT) may be a cost-effective way to test these concepts in a pilot study

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1. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-consent

2. Why is it so difficult to enroll patients in clinical trials? Normal Kanarek, Dina Lansey, Harold C. Agbahiwe, Julie R. Brahmer, Elizabeth M. Jaffee, Antonio C. Wolff, Vered Stearns, Michael Anthony Carducci, and Richard C. Zellars J of Clin Onc 2014: 32: 15 suppl

3. Riley DS, Barber MS, Kienle GS, Aronson JK, von Schoen-Angerer T, Tugwell P, Kiene H, Helfand M, Altman DG, Sox H, Werthmann PG, Moher D, Rison RA, Shamseer L, Koch A, Sun GH, Hanaway P, Sudak NL, Kaszkin-Bettag M, Carpenter JE, Gagnier JJ, CARE guidelines for case reports: explanation and elaboration.

4. https://globalforum.diaglobal.org/issue/april-2021/time-to-review-your-promotional-review/by Erica Dankiewicz