Congratulations to Alethea Wieland, President and Founder of Clinical Research Strategies and a member of the MedSurgPI team for co-authoring the attached publication: Real‐World Evidence to Support the Registration of a New Osteoporosis Medicinal Product in Europe, featured in Therapeutic Innovation & Regulatory Science. #osteoporosis #tymlos #fda #ema #regulatorydecision #realworlddata #realworldevidence #abaloparatide #eladynos #tymlos #medicalresearch
Practical Pointers
Practical Pointers: Product Development and Medical Affairs
Written by: Gerald L. Klein, MD; Burak Pakkal, MD, Roger E. Morgan, MD; Renu Jain, PhD; Shabnam Vaezzadeh, MD; Pavle Vukojevic, MD; Larry Florin, MBA; Victoria Manax, MD
Product Development
Data Monitoring Committees in Clinical Trials: The new FDA Guidance on “Use of Data Monitoring Committees in Clinical Trials” (DMC) just came out in February 2024. [1] The FDA strongly recommends using a DMC if there is a risk of a serious mortality or morbidity due to the participant’s medical condition or if the investigation may cause serious unexpected adverse events during the trial. The agency further states that the use of such a committee is practical.
MedSurgPI suggests that when the study is short in duration, a Safety Review Committee, (SRC) may be a more practical approach to further ensure safety of the clinical trial. This consists of a medical monitor, the principal investigator, and another medical safety expert.
Overview of Device Regulation: The FDA has just issued the “Quality Management System Regulation (QMSR) Final Rule”, which amends the good manufacturing practices requirements of the Quality System Regulation (21 CFR Part 820).[2]
Medical device manufacturers of US medical devices must adhere to the following:
US FDA Registration Guidance | US Medical Device Registration
Device Registration and Listing
Premarket Notification 510(k) unless exempt, or Premarket Approval (PMA)
Investigational Device Exemption (IDE) for clinical studies
Still a Need to Improve More Diverse Populations in Clinical Trials: Clinical Trials need to involve more diverse populations such as racial and ethnic minorities, the elderly, rural populations, women, etc.[3] The FDA has published a new guidance document that explains how this data is to be collected during a clinical trial: “Collection of Race and Ethnicity Data in Clinical Trials, and Clinical Studies for FDA-Regulated Medical Products: Draft Guidance for Industry.”[4] One resource, with tools and other information to help improve this situation, may be found at the National Institute of Minority Health and Health Disparities website.
Medical Affairs
Keeping Current: Presenting yourself as an expert goes beyond just understanding your product; it’s crucial to be deeply knowledgeable about the conditions it treats. This requires a commitment to continuously monitoring and analyzing relevant medical literature, including newsletters, attending conferences, and reviewing clinical trial data. Keeping abreast of advancements in the field ensures that you remain a comprehensive resource for both your product and its application. This ensures that your team can provide accurate and up-to-date information, establishing yourself as a reliable source.
AI Chatbots for Medical Education: Some medical information tasks can be automated by the use of AI chatbots for providing such information to health professionals and patients about medication and device indications, adverse effects, dosages, and drug interactions.
Medical Affairs Microgrants: Our experience suggests that a ‘microgrant’ program can be a useful tool in obtaining greater healthcare professional (HCP) engagement. This entails establishing a very modest grant program that allows HCPs who do not conduct formal clinical trials to defray the cost of such activities as creating an article (case history), small study (observational, history, etc.) of interest to your company.
[1] https://www.fda.gov/media/176107/download.
[3] Kim J and McDaniel D. From Words to Action: Advancing Efforts to Reduce the Racial Gap in Clinical Research. Applied Clinical Trials. Feb 7, 2024.
Practical Pointers Special Edition - Investment Essentials
Written by: Gerald L. Klein, MD; Roger E. Morgan, MD; Shabnam Vaezzadeh, MD; Pavle Vukojevic, MD; Burak Pakkal, MD; Michael Fath, PhD; Renu Jain, PhD; Larry Florin, MBA; Victoria Manax, MD
In light of the recent conclusion of the JP Morgan Healthcare Conference in San Francisco, a pivotal event for global investment, there’s a noticeable shift in focus among companies and investment groups. As they reassess strategies for raising capital and evaluating a wide spectrum of sectors - including biotech, tech, digital, device, pharmaceuticals, and diagnostic technologies - we find it timely and pertinent to dedicate this month’s Practical Pointers to these emerging trends, which are currently at the forefront of investor and founder discussions.
Fundamental Topics Related to the Technology and Pathway
What is the medical or technological need?
What is the background science?
Is there rational data proving the hypothesis?
What is the patent portfolio?
What is the regulatory pathway?
What is the clinical trial strategy/pathway?
What is the expected clinical benefit?
What is the reimbursement strategy?
Is there an experienced product development team running the organization?
What are the competitive products?
What is the exit strategy?
What is the market size?
What are the risks of the project?
What is the Medical Need? This is one of the most quintessential questions that helps determine the value of a scientific product. The more significant the medical need the more it may lead to quicker funding, quicker regulatory review, and more investigator engagement. For example, there is a huge need for better oncology treatments, so these products are highly valued, and a tremendous amount of venture capital is being poured into many of these companies. Meanwhile, cancer prevention is what has led to a recent reduction in cancer mortality in the U.S. Another example of a critical area is the need for vast improvement in cardiovascular disease.
What is the Science? Is the technology based on plausible and good scientific work? Can the results be replicated? What is the level of expertise of the scientists who have conducted the experiments? Is the scientific hypothesis convincing?
Is there Rational Data Proving the Hypothesis? Does the data support the hypothesis? Are there other plausible explanations for the observed effect? Does this stand up to critical scientific review?
What is the Patent Portfolio? What is the status of patent filings? Have provisional patents been filed? Are patents pending? Which countries are covered? How much longer do the patents last? Are the patents adequate to provide protection vis-a-vis current and future competition? Who owns the patents? If it is a university, what are the licensing terms? It is essential to answer the following questions: Are the patents on the composition of matter; formulation/process; methods of use; and is there confirmation of freedom to operate?
What is the Regulatory Strategy? Is the technology going to be regulated by the FDA? Will it require filing an Investigational New Drug (IND) application or an Investigational Device Exemption (IDE)? What regulatory division of FDA/EMA will review this? Is there potential for special designation; orphan drug, expedited review, breakthrough? Have you had preliminary discussions with FDA/EMA regarding regulatory and clinical pathways? Will Phase I be in a healthy normal population? At what stage will you attempt to obtain proof of concept?
What is the Clinical Strategy/Pathway? What kind of clinical data will be required? Do you have information from the FDA/EMA as to their requirements? How are you planning to generate the clinical data? Are there competitive products on the market or in development that will affect your development plan?
Will you utilize a contract research organization (CRO), fractional service providers, or your own team? Do you have the medical, clinical, and scientific expertise to create a clinical strategy to plan clinical development in the most direct, economic, and efficient manner? Will you work with academic institutions, a site management organization, and/or independent investigators? What will be the duration and expense of each clinical phase? What will be the geographic scope of the clinical program?
What is the Expected Clinical Benefit? Will this product significantly modify a disease, prolong life, improve quality of life, or have fewer side effects than current therapy? Will it improve disease diagnosis? In addition, are there pharmacoeconomic benefits of the product?
What is Your Reimbursement Strategy? Is the technology a novel product or a “me too” (one that closely imitates an existing product)? Will it treat a rare disease? If there are competing products on the market, does it have significant medical or economic benefits? Will it extend life or improve quality of life? Are there reimbursement codes or do you need to lobby for them? Are you planning to generate data for Medicare reimbursement if applicable? Who will provide reimbursement pathway advice to your team?
Do You Have an Experienced Product Development Team? How many people are on your team? Do you have full-time dedicated staff? Has your team developed similar products before? Have they attained a New Drug Application (NDA), Biologics License Application (BLA), or clearance? Does your group work in other countries besides the U.S.? What types of companies and roles has your senior leadership team been involved with in terms of their experience?
What are the Competitive Products? What are the competitive products already on the market or in development? What is your competitive advantage over them? How will they affect your clinical development, commercialization, and market potential? What other products are in development and how might they affect your development and/or commercialization strategy?
What is Your Exit Strategy? Are you planning to sell the product (or company) when you have demonstrated proof of concept? Will you try and obtain product approval before an exit? Do you intend to manufacture, and commercialize the technology yourself, seek partnership, hand off, or some combination in different geographies?
What is the Market Size? Have you identified your Total Addressable Market (TAM)? What is the overall market size, and which is your addressable market? Which geographies and populations will you target? What is your order of entry strategy? Would there be opportunities for expanding the market?
What are the Risks of the Project? Have you characterized the project risks across the full range of functional areas? Have these been quantified in a risk register? Do you have mitigations for the relevant risks?
Practical Pointers for Drug Development and Medical Affairs
Written by: Gerald L. Klein, MD: Burak Pakkal, MD; Roger E. Morgan, MD; Renu Jain, PhD; Shabnam Vaezzadeh, MD; Pavle Vukojevic, MD; Larry Florin, MBA; Victoria Manax, MD
Drug Development
In 2023, the U.S. Food and Drug Administration (FDA) published numerous significant guidance documents. Below is a selection of these key publications.
Numerous types of real-world data can be analyzed in non-clinical trials such as registries, electronic health records, medical claims, and data on products used in clinical practice as part of a package for FDA regulatory product approval.[1]
The FDA suggests the following:
Early engagement will allow for timely identification of challenges in the design and planning of a non-interventional study and for discussion of how such challenges might be addressed.
When submitting a meeting request, sponsors should include adequate information - as outlined in FDA guidance for formal meetings - for FDA to both assess the potential utility of a meeting and to identify relevant FDA subject matter experts who should address the proposed agenda items.
Optimizing the dosage for oncology products now requires a strong rationale for choice of dosage which should be provided before initiating registration trial(s):
To support a subsequent indication and usage:
Especially for oncologic diseases not adequately represented in completed dose-finding trials or for new combination regimens.
If sufficient rationale for choice of dosage cannot be provided, additional dose-finding should be conducted.[2]
The FDA further states that different dosages may be needed in different disease settings or oncologic diseases based on potential differences in tumor biology patient population, treatment setting, and concurrent therapies (for combination regimens), among other factors.
Applicable nonclinical and clinical data should be considered to support the proposed.
Different dosages may be needed in different disease settings or oncologic diseases based on potential differences in tumor biology, patient population, treatment settings, and concurrent therapies (for combination regimens), among other factors.
Applicable nonclinical and clinical data should be considered to support the proposed.
For additional information, please see FDA’s Project Optimus:
When developing drugs for rare indications, the FDA frequently allows the use of innovative trial designs. These should be discussed with the appropriate division very early on. This may include Bayesian methods, n-of-1 clinical studies, randomized delayed-start designs, crossover designs, and master protocol.[3] These studies require a detailed statistical analysis plan including key features of the clinical investigation design and preplanned analysis discussed with the review team before the study initiatives.
Canadian Regulatory Pointers
On December 4, 2023, Health Canada’s Regulatory Operations and Enforcement Branch revised the medical device establishment licence (MDEL) application form. The form is used to:
Apply for an MDEL
Apply for an MDEL after a cancellation
Submit changes to your existing MDEL
Cancel your MDEL
Apply for a reinstatement of your MDEL after a suspension
For specific details, visit the following website: https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/establishment-licences/medical-devices-compliance-bulletin/updates-frm0292-instructions.html
Medical Affairs
Direct-to-Consumer Prescription Drug Advertisements in television and radio in new guidance document:[4]
First Standard: The major statement is presented in consumer-friendly language and terminology is readily understandable.
Second Standard: The major statement’s audio information, in terms of the volume, articulation, and pacing used, is at least as understandable as the audio information presented in the rest of the advertisement.
Third Standard: In advertisements in television format, the major statement is presented concurrently using both audio and text.
Fourth Standard: In advertisements in television format, for the text portion of the major statement, the size and style of font, the contrast with the background, and the placement on the screen allow the information to be read easily.
Fifth Standard: During the presentation of the major statement, the advertisement does not include audio or visual elements, alone or in combination, which are likely to interfere with comprehension of the major statement.
1. Considerations for the use of real-world data and real-world evidence to support regulatory decision-making for drug and biological products. Guidance for Industry. August 2023.
2. Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases. Guidance for Industry January 2023.
3. Rare Diseases: Considerations for the development of drugs and biological products. Guidance for industry. December 2023.
4. Direct-to-consumer prescription drug advertisements: presentation of the major statement in a clear, conspicuous, and neutral manner in advertisements in television and radio format final rule Q&A. Guidance for Industry December 2023.
Practical Pointers for Drug Development and Medical Affairs
Written by: Gerald L. Klein, MD: Burak Pakkal, MD; Roger E. Morgan, MD; Renu Jain, PhD; Shabnam Vaezzadeh, MD; Pavle Vukojevic, MD; Larry Florin, MBA; Victoria Manax, MD
Drug Development
Canada offers advantages for conducting clinical trials within its borders, including:
Advanced infrastructure
High quality investigators coupled with advanced hospital facilities and research centers significantly bolsters Canada’s stature in scientific exploration
Health Canada’s 30-day target for reviewing Clinical Trial Applications
Health Canada also offers a 7-day review option for eligible comparative single-dose bioavailability/bioequivalence studies
Canada has the second lowest cost among G7 nations for managing clinical trials and is ranked #1 in active clinical trials per capita [1]
FDAs Patient-Focused Drug Development defines a patient reported outcome (PRO) as a type of clinical outcome assessment used to collect patient experience data. [2] It is a measurement based on a report that comes directly from the patient about the status of a patient’s health condition without interpretation of the patient’s response by a clinician.[3]
In oncology studies, when the PRO objective is clinical benefit, the percentage of each disposition category should be calculated using the randomized population as the fixed denominator. The PRO measure is expected to be completed by patients with various statuses such as: [4]
Patients who are on therapy
Patients who discontinue from treatment due to disease progression, adverse event, or other reasons as specified in the protocol
Patients who were randomized but not treated
Patients who paused treatment
In our opinion, it is advantageous for nursing students to be introduced to clinical research as part of their training This exposure allows them to acquire experience in comprehending and analyzing scientific literature, ultimately leading to an enhanced ability to interpret drug or device package inserts. Nurses may develop a greater understanding of pharmacokinetics, and dose range activity affecting efficacy and toxicity. Our biggest hope is that some of these students will develop a passion for clinical research and make a career of it.
Medical Affairs
The appropriate distribution of unapproved uses for approved or cleared drugs/devices has been difficult to navigate. The FDA has a new Draft Guidance: Communications from Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products Questions and Answers. [5] This was released in October 2023 and helps to clarify many aspects of this important medical affairs area. It is strongly recommended reading for all medical affairs professions.
The importance of medical affairs (MA) in fostering the greater uptake of vaccines cannot be overstated. MA not only provides health care providers (HCP) with the latest data about their vaccines but also helpful techniques to educate their patients about the benefits of those potentially lifesaving compounds. They can help the PCP present objective information about the pros and cons of this therapy.
Small pharmaceutical companies that lack a large sales force to promote their products may be able to offset this challenging dilemma with a strong medical affairs team and a limited number of experienced medical liaisons. Coupled with an assertive digital communication plan, this approach may be able to compensate for the lack of sales force with a creative marketing and sales strategy.
https://www.investontario.ca/pharmaceuticals#clinical-trials.
21st Century Cures Act section 3001.
https://www.fda.gov/durg/development-approval-process-drugs-fda-patient-focused-drug-devvelopment-guidance-series-
enhancing-incorporation-patients-voice-medical.
Submitting Patient -Reported Outcome Data in Cancer Clinical Trials: Guidance for Industry. Technical Specifications Document. CDER November 2023.
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs.
Dr. Gerald Klein: Speaker and Poster Presentation at SOCRA 2023 Annual Meeting
Improving Informed Consent Forms in Clinical Trials
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:
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.
Klein GL. The case for digital pill use in clinical trials. Clin Trial Pract Open J. 2021; 1(1): 89-94
Butryn, Tracy, et al. “Keys to success in clinical trials: A practical review.” International Journal of Academic Medicine 2.2 (2016): 203.
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).
Riley, David s., et al. “CARE guidelines for case reports: explanation and elaboration document.” Journal of clinical epidemiology 89 (2017) 218-235.
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
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.
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
——————————————-
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-consent
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
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.
https://globalforum.diaglobal.org/issue/april-2021/time-to-review-your-promotional-review/by Erica Dankiewicz
Safety and Pharmacovigilance Tips
These Safety and Pharmacovigilance tips are aimed at improving the understanding of this area of clinical drug and device development. For example, clinical sites are frequently confused about the nuances of adverse event reporting, assessing causality, or the use of proper safety terminology. In addition, some sponsors may not be using the appropriate type of committee to oversee the safety of their clinical trial. See below for the first tip in this series and feel free to reach out to us with any questions: info@medsurgpi.com.
Clinical Investigators and their sites should establish a systematic way of assessing causality when adverse events and serious adverse events occur. The Bradford Hill criteria are an established practical way of determining these events[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.
Consistency: Established adverse event attributions or previous determinations in similar situations indicate causation.
Specificity. An established mechanism of action connecting the treatment and the adverse event indicates causation.
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.
Biological Gradient: a dose response effect is a strong argument for causation.
Plausibility: the causal relationship is biologically plausible.
Coherence: the known facts fit the natural history and biology of the disease.
Experiment: Epidemiologic studies indicate causation.
Analogy: a similar agent causes the same type of AE.
[1] Klein, G., Johnson, P. and Morgan R., Medical Monitoring of Clinical Research Studies. J. Clin. Res. Best Practices. 2021: Vol 17 (1)
Tips For Being A Good Medical Monitor
Gerald L. Klein, MD and Roger Morgan, MD
PROMPT RESPONSE TO INVESTIGATOR SITE QUESTIONS
Answering questions about inclusion and exclusion (I/E) is an important function of the medical monitor.
A prompt response is necessary if the patient is waiting to be screened.
A clear explanation of your response
Document with the specific I/E criteria
Provide clear documentation for the Trial Master file/investigator and, if appropriate, furnish a reference article from the medical literature
If patient safety is involved, providing a quick response is crucial.
Examples of when a quick response is necessary:
Suspected Unexpected Serious Adverse Reaction (SUSAR)
If a question about the necessity of unblinding occurs
Serious adverse event that triggers the study to be stopped
A safety issue that needs to be discussed immediately with the site and or sponsor
It is important to have a backup medical monitor in place to provide this service continuously.
Provides coverage for holidays, vacations, or sick days
PROVIDING MEDICAL REFERENCES
Why provide medical or regulatory references?
To foster greater understanding of the entry criteria
To help the sites form better decisions in the future
To create mutual respect between the sites and the medical monitor
To help with better regulatory understanding of the study
ANSWERING QUESTIONS
All questions from the sites should be added to a Question and Answer log (Q&A) and made available to other monitors who may be on the study as well as to clinical operations personnel.
This will ensure consistency and will help address future questions that are similar
Help the site decide about entrance criteria
May clarify some common questions that sites may have
Promotes minimization of protocol deviations
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.
MedSurgPI partners with Exquisite Biomedical Consulting to Offer Medical Consulting to Canadian Life Sciences and Medical Technology Companies
MedSurgPI, LLC partners with Exquisite Biomedical Consulting to provide Medical Affairs and Medical Communication services to the Canadian pharmaceutical, biotechnology, medical device and related technology companies and institutions.
Exquisite Biomedical Consulting, based in Vancouver, British Columbia offers a comprehensive suite of Medical Affairs and Medical Communication Services such as Medical Affairs Strategy, KOL and publication strategy, advisory panel strategy and execution, MSL training, due diligence for business development, medical writing of Clinical Evaluation Reports (EU MDR and MDD), white papers and manuscripts.
MedSurgPI offers part time Chief Medical Officer, Medical Monitoring, and Medical Consulting for Product Development and Medical Affairs for Drug, Biologic, and Device companies.
In addition, Shabnam Vaezzadeh, MD, MPA, BCMAS, CEO of Exquisite Biomedical Consulting will head up the medical writing and publications groups for MedSurgPI.
For more information contact Exquisite Biomedical Consulting: https://lnkd.in/dYV4zGbC / contact@exquisitebiomedical.com. MedSurgPI info: www.medsurgpi.com / svanvactor@medsurgpi.com.
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.
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…
White Paper Published in DIA
The Extraordinary Problem of Medication Nonadherence in Oncology Patients and How Digital Pills Can Make a Difference. Available to download.
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.
Dr. Gerry Klein to serve as panelist on Webinar: Wound Infection in Humanitarian Emergencies
#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
Potential Psychological Benefits of a Regenerative Graft for Nipple Reconstruction
Link to this article appearing in the Journal of Aesthetic & Reconstructive Surgery ISSN 2472-1905
by Gerald L. Klein and Peter C. Johnson
Vol. 7 No.2:17