Placebo Effect versus Nocebo Effect

In placebo-controlled clinical trials, a placebo refers to an inactive or inert substance or treatment that has no specific therapeutic effect on a person's health condition but is given or administered with the intention of maintaining the blinding of the study (i.e., the participants and/or investigators do not know if the active treatment or placebo is given). Placebo can be in the form of a pill (sugar pill), injection, or any other treatment method that resembles a real medical intervention. However, during the clinical trial, the placebo may have a therapeutic effect and have an impact on the outcome measures. 

The placebo effect is defined as a beneficial effect experienced by a clinical trial participant due to receiving a placebo (inactive substance) believing it to be an active treatment. The placebo effect has been discussed quite extensively in the literature. I posted several articles to discuss the placebo effect in placebo-controlled clinical trials. 

• Placebo Effect, Honest Placebo, Open-label Placebo
• Placebo effect and its impact on the overall treatment effect
• Placebo Effect and The Choice of Placebo

Now there is a term 'nocebo effect' (it is not a typo). In a newly released draft guidance by FDA "Psychedelic Drugs: Considerations for Clinical Investigations", the 'nocebo effect' is specifically mentioned: 

An AWC study uses a design that permits a valid comparison with a control to provide a quantitative assessment of a drug’s effect. In the context of psychedelic drug development, the use of a traditional placebo as a control can be problematic for assessing efficacy. Subjects receiving an active drug experience functional unblinding because of the intense perceptual disturbances that can develop; those who receive a placebo in the context of high expectancy may experience a nocebo effect (i.e., worsening symptoms as a result of knowing they did not get active treatment). However, an inactive control allows for better contextualization of any safety findings. Alternatives to an inert placebo (e.g., subperceptual doses of a psychedelic drug, other psychoactive drugs that mimic some aspects of the psychedelic experience) may be considered as well. 

The nocebo effect is defined as a negative effect experienced by a clinical trial participant due to receiving a placebo (inactive substance) believing it to be a harmful treatment. With the help of the ChatGPT, the following table compared the differences between the placebo effect and the nocebo effect. 

Aspect	Placebo Effect	Nocebo Effect
Definition	A positive response to an inactive treatment, often due to the person's belief in the treatment's effectiveness.	A negative response to a treatment, often due to the person's belief that the treatment will cause harm or have adverse effects.
Psychological Mechanisms	Expectation of improvement, conditioning, and the power of suggestion.	Expectation of harm, conditioning, and the power of suggestion.
Potential Chemical Mechanisms	Belief and expectation trigger the release of endorphins, dopamine, and other neurochemicals, leading to perceived improvement in symptoms.	Belief and expectation trigger the release of stress hormones (e.g., cortisol) and activate the brain’s pain pathways, leading to perceived worsening of symptoms.
Common Occurrences	In clinical trials, as a control group receiving an inactive treatment (e.g., sugar pill).	In clinical trials, when participants experience side effects despite receiving an inactive treatment, or when they're informed about potential side effects
Impact on Treatment	Can lead to an actual improvement in symptoms or a perceived improvement in well-being	Can cause or exacerbate symptoms, leading to a perceived worsening of health
Importance in Research	Helps determine the true efficacy of a treatment by comparing it to the placebo group	Highlights the importance of considering participants' expectations and beliefs when designing and interpreting clinical trials.
Clinical Use	Utilized in clinical trials as a control to assess the effectiveness of new treatments.	Considered a challenge in clinical trials as it can lead to false negative outcomes or increased reports of adverse effects.
Impact on Clinical Trial Outcome	Making the outcome measures in placebo group artificially better than what they should be. Underestimating the treatment difference. Lowering the statistical power.	Making the outcome measures in placebo group artificially worse than what they should be. On the efficacy side, overestimate the treatment difference. Increasing the statistical power.
Ethical Considerations	May be considered deceptive if participants are not informed about the possibility of receiving a placebo	Raises questions about the balance between informing participants of potential side effects and avoiding the creation of negative expectations
Examples	- Feeling relief from pain after taking a sugar pill, believing it to be a painkiller. - Experiencing reduced anxiety after receiving a fake treatment, thinking it is an anti-anxiety medication.	- Developing side effects (e.g., nausea, dizziness) after taking a harmless sugar pill, convinced it is a potent medication. - Perceiving worsening of symptoms despite receiving an inert substance, assuming it is a harmful treatment.

References: 

• Wartolowska, Colloca, and Amandzio (2023) Editorial: The nocebo effect and its consequences for clinical trials and clinical practice
• Colloca and Barsky (2020) Placebo and Nocebo Effects
• Colloca and Miller (2011) The nocebo effect and its relevance for clinical practice
• Ferreres, Banos, and Farre (2004)Nocebo effect: the other side of placebo.
• Mitsikostas (2009) Nocebo is the enemy, not placebo. A meta-analysis for the nocebo effect in headaches
• Amanzio, Corazzini, Vase, & Benedetti (2016). A systematic review of adverse events in placebo groups of anti-migraine clinical trials. 
• Wolters, Peerdeman, and Evers (2019) Placebo and Nocebo Effects Across Symptoms: From Pain to Fatigue, Dyspnea, Nausea, and Itch
• Hoffman, et al (2022) Vaccine hesitancy prospectively predicts nocebo side-effects following COVID-19 vaccination

SAE reporting - from non-serious AE to serious AE - one event or two events?

An adverse event is any undesirable experience associated with the use of a medical product in a patient. The event is serious (therefore serious adverse event (SAE)) and should be reported when the patient outcome is:

Death

Report if you suspect that the death was an outcome of the adverse event, and include the date if known. 

Life-threatening

Report if suspected that the patient was at substantial risk of dying at the time of the adverse event, or use or continued use of the device or other medical product might have resulted in the death of the patient.

Hospitalization (initial or prolonged)

Report if admission to the hospital or prolongation of hospitalization was a result of the adverse event.

Emergency room visits that do not result in admission to the hospital should be evaluated for one of the other serious outcomes (e.g., life-threatening; required intervention to prevent permanent impairment or damage; other serious medically important event).

Disability or Permanent Damage

Report if the adverse event resulted in a substantial disruption of a person's ability to conduct normal life functions, i.e., the adverse event resulted in a significant, persistent or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities and/or quality of life.

Congenital Anomaly/Birth Defect

Report if you suspect that exposure to a medical product prior to conception or during pregnancy may have resulted in an adverse outcome in the child.

Required Intervention to Prevent Permanent Impairment or Damage (Devices)

Report if you believe that medical or surgical intervention was necessary to preclude permanent impairment of a body function, or prevent permanent damage to a body structure, either situation suspected to be due to the use of a medical product.

Other Serious (Important Medical Events)

Report when the event does not fit the other outcomes, but the event may jeopardize the patient and may require medical or surgical intervention (treatment) to prevent one of the other outcomes. Examples include allergic brochospasm (a serious problem with breathing) requiring treatment in an emergency room, serious blood dyscrasias (blood disorders) or seizures/convulsions that do not result in hospitalization. The development of drug dependence or drug abuse would also be examples of important medical events.

In clinical trial setting, there are two layers of SAE reporting:

The investigational site reports the SAE to the trial sponsor:

According to ICH E6 (Good Clinical Practice), the SAEs should be reported immediately to the sponsor when the site staff become aware of the occurrence of a SAE. 'Reported immediately' is generally interpreted as 'reported within 24 hours'. The clinical trial protocol typically includes a statement "Sites must report SAE information regardless of causality or expectedness to the Sponsor within 24 hours of awareness of an SAE." 

The sponsor or designee reports the SAEs and SUSAR to the regulatory authorities (FDA):

SAEs need to be reported to regulatory agencies and IRBs/ECs in narrative format (so called SAE narratives). According to 21CRF part 312.32 Safety Reporting, here are the requirements:

SUSUR stands for serious and unexpected suspected adverse reaction. FDA guidance "Safety Reporting Requirements for INDs and BA/BE Studies" provided the definition for SUSAR and specified the reporting requirement. 

SUSAR determination and subsequent reporting are typically handled by the drug safety or pharmacovigilance group, which has access to treatment assignment information. When a SUSAR event is reported, the drug safety or pharmacovigilance group may unblind the individual subject to determine if they are in the active drug group or the placebo group. If the subject is in the placebo group, it will not be considered a SUSAR.

SUSAR events that involve unexpected fatal or life-threatening suspected adverse reactions must be reported to the FDA within 7 days through the submission of a "7-day IND safety report." Here is what is said in 21CFR part 312.32 IND Safety Reporting:

In practice, it is common for adverse events to initially present as non-serious (not meeting the criteria for defining a serious adverse event), but with the event worsening, they may evolve into a serious adverse event. For example, a subject may experience an adverse event that eventually requires hospitalization, meeting the criteria for a serious adverse event.

There is a common (but inappropriate) approach to handling this situation by splitting the event into two separate entries: one for the initial non-serious adverse event and another for the subsequent serious adverse event. Some sponsors provide instructions to record the non-serious adverse event with a stop date, mark the outcome as 'Not recovered/not resolved,' and create a new entry for the serious adverse event with the start date when the seriousness criteria are met. The stop date of the non-serious adverse event should be the same date or the day prior to the start date of the serious adverse event. While this approach aligns with SAE reporting and is considered conservative, it artificially divides the same episode into two separate events, which will cause the problem when writing the SAE narratives. We can not just write a SAE narrative without including the non-serious part - they are essentially the same event. 

In general, when an adverse event initially presents with non-serious symptoms and later progresses to meet the criteria for a serious adverse event (SAE), it is typically reported once as an SAE. This is because the serious adverse event designation takes precedence over the non-serious symptoms.

It's important to note that the onset date of the SAE should be the date when the symptoms started, not the date when the SAE criteria are met. Reporting of SAEs should be based on the date when the SAE criteria are met and when the site staff becomes aware of the SAE.

In situations where an adverse event starts as non-serious and progresses to serious, it is appropriate to report the event as an SAE.

When an adverse event evolves into a serious condition, such as requiring hospitalization or meeting other predefined criteria for seriousness, it is considered a new phase or stage of the same event. Reporting it as an SAE captures the escalated severity and ensures appropriate attention, monitoring, and reporting to regulatory authorities.

When an adverse event (AE) starts as non-serious and progresses to a serious state, it should be reported solely as a serious adverse event (SAE). In this situation, there are three potentially relevant dates: the "serious adverse event start date," "adverse event becomes serious," and "the site staff became aware of the serious adverse event." These terms are associated with the reporting and monitoring of adverse events in clinical trials or medical research. Here's a comparison of these terms:

Serious Adverse Event Start Date: The serious adverse event start date refers to the specific date when an adverse event initially occurred or began in a participant during a clinical trial or medical research study. It marks the beginning of the event's timeline and is often recorded to establish the temporal relationship between the event and the study procedures.

Adverse Event Becomes Serious: An adverse event refers to any unfavorable or undesirable medical occurrence experienced by a participant during a clinical trial or medical research study, regardless of its seriousness. When an adverse event becomes serious, it means that the event has worsened in intensity, severity, or clinical impact. The criteria for determining whether an adverse event is considered serious may vary, but they generally include outcomes such as death, life-threatening situations, hospitalization or prolonged hospital stay, significant disability, congenital anomalies, or other important medical events.

The Site Staff Became Aware of the Serious Adverse Event: This phrase signifies the point at which the staff at the clinical trial site or research facility becomes aware of the occurrence of a serious adverse event in a participant. It is crucial to promptly report and document the event to ensure participant safety and adhere to regulatory requirements. The site staff's awareness triggers subsequent actions such as assessment, documentation, reporting to the appropriate authorities, and potential modifications to the study protocol or participant management.

In summary, when an adverse event starts as non-serious and progresses to a serious state, it should be reported solely as a serious adverse event (SAE). The serious adverse event start date marks the initial occurrence of the event, while the "adverse event becomes serious" indicates the worsening of its intensity or impact. The "site staff became aware of the serious adverse event" signifies the point when the research facility staff acknowledges the occurrence and initiates the necessary actions for reporting and participant safety.

Regulatory Education for Industry (REdI) Annual Conference 2023 - Slides and Recordings

Early this month, FDA conducted 'Regulatory Education for Industry (REdl) Annual Conference 2023'. This annual conference provided opportunity for health care industry professionals to Learn directly from the FDA’s regulatory experts in medical product centers: drugs, devices, and biologics. The course from annual conference is designed to provide participants with a strong, basic foundation in the FDA’s regulatory requirements, and also create awareness of current activities.

• The flyer about this conference: https://www.fda.gov/drugs/news-events-human-drugs/regulatory-education-industry-redi-annual-conference-2023-06052023
• The agenda for the conference: https://sbiaevents.com/files2023/REdI-2023-Agenda.pdf

All the FDA presentation can be watched on Youtube and the presentation slides are listed in the tables. 

There are two presentations by FDA statisticians: Dr Andrew Potter on "Reviewer’s Perspective on Data Collected by Wearable Digital Health Technology in Clinical Trials" and Dr John Scott on "FDA’s Implementation of the Estimand Framework and Complex Innovative Trial Design Meeting Program".

Plenary + Drugs Day 1:

User Fee Impact on FDA Programs Jeff Shuren, Patrizia Cavazzoni, Peter Marks

Biosimilar Program Updates and What’s New Under BsUFA III Stacey Ricci and Kimberly Maxfield

FDA Formal Meetings: What’s New under PDUFA, BsUFA, and OMUFA Elizabeth Thompson

Electronic Submission Gateway (ESG): The Road to Modernization Jessica Bernhardt

ECTD v4.0 Implementation Update Jonathan Resnick

eCTD: More than a Document Heather Crandall

CDER-CBER Data Standards Program Ray Wang

Reviewer’s Perspective on Data Collected by Wearable Digital Health Technology in Clinical Trials Andrew Potter

PDUFA VII Goals For Digital Health Technologies – A Technical Perspective Marry Ann Slack

Drugs Day 2: 

Leveraging Small Business and Industry Assistance (SBIA) Resources Renu Lal

Overview of FDA Split Real Time Application Review (STAR) Pilot Program LaShawn Schnupp

Use-Related Risk Analysis (URRA) and Human Factors (HF) Protocol Reviews: What to Submit for an Efficient Review Lolita Sterrett

The Modernization of Clinical Trials through Digital Health Technologies (DHTs), Decentralized Clinical Trials (DCTs), and Point of Care Trials Elizabeth Kunkoski

PDUFA VII Real-World Evidence Kimberly A. Smith

New PDUFA VII Commitments: Pre-approval & Post-approval Postmarketing Requirements (PMRs) Kathleen Weil

How CDER is Accelerating Rare Disease Cures and the PDUFA VII Rare Disease Endpoints Advancement Pilot Program Kerry Jo Lee

Chemistry, Manufacturing, and Controls Assessment for Expedited Programs Paresma Patel

Best Practices for Drug Product Recalls Doris Chin

Devices Day 1:

Medical Device Regulatory Framework: Where to Start? Kendra Holter

Biocompatibility Basics Jennifer Goode

Streamlining Conformity Assessment: Putting Standards to Work Scott A. Colburn

Detangling the 510(k) Process Andrew Sprau

CDRH Portal Overview and Feature Walkthrough Nelson Anderson

Reduced Medical Device User Fees: Small Business Determination (SBD) Program Jason Brookbank

Managing Medical Device Nonconforming Product with Quality Ruth Bediakoh

Handling Medical Device Compliant Files with Quality Tonya Wilbon

Devices Day 2/Biologics Day 1:

Addressing Regulatory Science Gaps in Artificial Intelligence (AI) / Machine Learning (ML) Alexej Gossmann

Radiation-Emitting Medical Device Update Laurel Burk

CDRH Medical Device Import Overview Yvette Montes

All about the Form FDA 483 and the ORA Electronic Reading Room William Chang

PDUFA VII Enhancements - Interaction with OTP Mara Miller

Overview of PREA, PSPs plus an Introduction to the Rare Pediatric Disease (RPD) Priority Review Voucher Program Adrienne Hornatko-Munoz

Nonclinical Development for Cellular and Gene Therapy Products from the Perspective of CBER/FDA Ernesto F. Moreira

Nonclinical Considerations for the Development of Cell and Gene Therapy Products for IND Submissions Gregory Conway

Clinical Readiness for IND Submissions Shelby Elenburg

Design Considerations for Clinical Trials in Rare Diseases

Rosa Sherafat

 

Biologics Day 2:

CMC Development and Readiness Pilot (CDRP) Program Ramjay S. Vatsan

CMC Considerations for Tissue Engineered Product Development Wen (Arron) J. Seeto

Identifying and Controlling Attributes Related to Potency for Cell and Gene Therapy Products Matthew Klinker

FDA’s Implementation of the Estimand Framework and Complex Innovative Trial Design Meeting Program John Scott

Postmarketing Safety and Pharmacovigilance for Vaccines Meghna Alimchandani

Expanded Access to Investigational Drugs for Treatment Use Lei Xu

CBER Inspections of Facilities for Biological Products Wei Wang

Resubmission of NDA/BLA After CRL: Class 1 versus Class 2 resubmission

If new drug application (NDA) or biological license application (BLA) is not approved by the FDA, the sponsor will receive a complete response letter (CRL). FDA's CRL letter will state something like "the application could not be approved at this time based on [issues and deficiencies]". Receiving a CRL is not the end of the world and the sponsor can address the issues and deficiencies and resubmit the NDA/BLA. Many NDA/BLAs were approved after the resubmission. 

It may take the sponsor months/years to address the issues and deficiencies before NDA/BLA can be resubmitted. However, once the NDA/BLA is resubmitted, the time leading to the PDUFA date is predicable. FDA's policy is to classify the resubmission into one of two classes: class 1 and class 2. 

Resubmission was discussed in 21 CFR Part 314.110 "Complete response letter to the applicant":  

FDA has a MAPP (Manual of Policies and Procedures) specifically about the classification of the NDA/BLA resubmission "Classifying Resubmissions of Original NDAs, BLAs, and Efficacy Supplements in Response to Complete Response Letters". The MAPP listed the items qualifying for class 1 and 2 resubmission.

The review time leading to the PDUFA date is 4 months longer for Class 2 than Class 1 resubmission. Four months seem to be short, but sometimes can be critical if there are competitive NDA/BLA submissions in the same therapeutic area. This is why there is a priority review designation and a priority review voucher program - both will shorten the FDA review time by 4 months. 

Here is an example of resubmission with Class 1 category and an example of resubmission with Class 2 category:

LIPOCINE ANNOUNCES ITS PARTNER RECEIVED FDA ACCEPTANCE OF NDA RESUBMISSION FOR TLANDO® 

"...announcing that the U.S. Food and Drug Administration (“FDA”) has accepted its New Drug Application (“NDA”) resubmission for TLANDO® (testosterone undecanoate). The FDA designated the NDA as a Class 1 resubmission with a two-month review goal period and set a target action date of March 28, 2022, under the Prescription Drug User Fee Act (PDUFA). Lipocine licensed the exclusive U.S. rights for TLANDO® to Antares Pharma."

Ardelyx Announces FDA Acceptance and Six-Month Review for Resubmission of its New Drug Application of XPHOZAH® (tenapanor)

"...the U.S. Food and Drug Administration (FDA) has accepted its resubmission of a New Drug Application (NDA) for XPHOZAH® (tenapanor) for the control of serum phosphate in adult patients with chronic kidney disease on dialysis who have had an inadequate response or intolerance to a phosphate binder therapy. The FDA has determined that the NDA is a class 2 review, which results in a six-month review period from the date of resubmission...."