Apr 10

2019 March FDA Guidances

Special Interest Guidances/Information Date Posted
Pediatric Information Incorporated Into Human Prescription Drug and Biological Products Labeling Good Review Practice – Final Guidance 27 Mar 2019
Standards Development and the Use of Standards in Regulatory Submissions Reviewed in the Center for Biologics Evaluation and Research – Final Guidance 25 Mar 2019
Rare Diseases: Natural History Studies for Drug Development – Draft Guidance 22 Mar 2019
Pediatric HIV Infection: Drug Development for Treatment – Final Guidance 19 Mar 2019
Human Immunodeficiency Virus-1 Infection: Developing Systemic Drug Products for Pre-Exposure Prophylaxis – Final Guidance 19 Mar 2019
Medical Devices Containing Materials Derived from Animal Sources (Except for In Vitro Diagnostic Devices) – Final Guidance 15 Mar 2019
A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers – Draft Guidance 14 Mar 2019
Severely Debilitating or Life-Threatening Hematologic Disorders: Nonclinical Development of Pharmaceuticals – Final Guidance 14 Mar 2019
Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products – Final Guidance 14 Mar 2019
Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials – Final Guidance 12 Mar 2019
Cancer Clinical Trial Eligibility Criteria: Minimum Age for Pediatric Patients – Draft Guidance 12 Mar 2019
Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies – Draft Guidance 12 Mar 2019
Cancer Clinical Trial Eligibility Criteria: Brain Metastases – Draft Guidance 12 Mar 2019
Nonproprietary Naming of Biological Products – Draft Guidance 07 Mar 2019
Upcoming Meetings (* = New)
* April 25, 2019: Antimicrobial Drugs Advisory Committee Meeting Announcement
* April 26, 2019: Antimicrobial Drugs Advisory Committee Meeting Announcement
* May 8, 2019: Meeting of the Pulmonary-Allergy Drugs Advisory Committee Meeting Announcement

Last updated: 09 April 2019

Mar 22

Does the FDA Esketamine Approval Open the Door for Enrichment Trial Designs in Psychiatry?

By Greg Hileman, Ph.D, Senior Director of Regulatory Affairs and Principle Regulatory Scientist at Cato Research


On March 5, the FDA approved Spravato (esketamine) nasal spray, for use in conjunction with an oral antidepressant for treatment-resistant depression. Esketamine is the s-enantiomer of ketamine, approved in the 1970’s as an anesthetic, but used off-label since the 1990’s for treating depression. Because of the risk of serious adverse outcomes resulting from sedation and dissociation caused by esketamine administration, and the potential for abuse and misuse of the drug, it is only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS).

Of importance to the development of products in the Division of Psychiatric Products (DPP), the efficacy of esketamine was established in one short-term study (two other, similar short-term trials did not meet the pre-specified statistical tests for demonstrating effectiveness) and one longer-term maintenance-of-effect trial using a randomized withdrawal study design. In this latter study, patients with a stable response while taking esketamine plus an oral antidepressant were re-randomized, with a portion of the group switched to placebo. Patients remaining on esketamine experienced a statistically significantly longer time to relapse of depressive symptoms than patients switched to placebo.

This approval based on an enriched study design was one of the first for the DPP. Industry and FDA have long debated the utility of enriched study design as providing substantial evidence of efficacy. The key issue identified by FDA statisticians is in controlling type 1 error with stepwise randomization schema and subsequently generalizing results from an enriched population to a general population as key. Various enrichment strategies have been proposed to address the large and growing placebo effect in psychiatry clinical trials. FDA guidance on clinical trial designs encourages the exploration of enrichment and other adaptive study designs in Phase 2, but cautions against relying on such trials for generating pivotal evidence of efficacy.

One can speculate that the approval of esketamine for depression may have political roots, since it allows FDA to exercise enforcement authority over the widespread off-label use of ketamine, now that seriously ill patients have a safe and effective approved product in this space. We are optimistic that the approval of esketamine on the basis of this randomized withdrawal maintenance study may herald a new FDA attitude on the topic supported by incoming Acting Division Director Tiffany Farchione, whose first public appearance in that role was at the 12 February Psychiatric Products Advisory Committee Meeting reviewing esketamine. In her opening remarks, Dr. Farchione explicitly stated that the Division considered the randomized withdrawal study to be “adequate and well controlled” for purposes of providing substantial evidence of effectiveness.

The strength of these remarks bodes well for patients suffering a variety of psychiatric disorders where placebo effects have been attributed to the failure of clinical trial not only in depression, but also in anxiety disorders, schizophrenia and most conditions where structured patient interviews serve as the primary endpoints.



Mar 20

FDA Approval of New Opioid Drug (DSUVIATM) Stirs Controversy – Is it Necessary or Not?

By Dieanira Erudaitius, Ph.D., Scientist at Cato Research

The United States Food and Drug Administration (FDA) granted approval of the opioid analgesic DSUVIATM on 02 November 2018.[[1]] Its intended use is for adults only where acute pain management has no alternative treatment other than an opioid analgesic.

DSUVIATM is a sublingual tablet containing sufentanil as the active pharmaceutical ingredient (API), a Schedule II controlled substance.[[2]] Sufentanil is an analogue of fentanyl; however, unlike fentanyl that has a potency of 100 times that of morphine, sufentanil is 1,000 times more potent.[[3]] While its potency raises concerns regarding addiction and misuse, advocates for the drug point out that sufentanil is currently already used in the hospital setting where it is intravenously delivered. Intravenous delivery (i.v.) of opioids does provide advantages such as providing immediate relief to the patient; however, it also has risks associated with dosing (e.g., issues have been reported of overdosing the patient).[[4]] DSUVIATM is unique because of its alternative sublingual oral form of delivery [[5]], which advocates argue is more easily controlled for dosing.

Opioids, regardless of the potency, raise concerns because of the risks associated with addiction, abuse, and misuse. Opponents to DSUVIATM’s approval point out that the pill form of the opioid makes it easily divertible. Illicit diversion is not at all uncommon, and is especially a problem for opioids.[3] While the FDA does not have a way to control or prevent this specific type of abuse, the agency did put strong limitations on its use. The FDA required an additional Risk Evaluation and Mitigation Strategy (REMS) from the manufacturer to ensure any risk from accidental exposure is adequately controlled.[[6]] Further, DSUVIATM has been approved for use only in certified, medically-supervised healthcare settings. These settings include emergency rooms (ERs), hospitals, and surgical centers where a certified healthcare provider is to administer the drug.[2]

Many medical experts and advocates in favor of opioid control question whether there was really a need to bring an additional opioid drug to the market. A common argument for the need of a more potent opioid is that oligoanalgesia (the inadequate treatment of pain) does remain a prominent issue in the hospital setting, especially for patients admitted to the ER. Proponents believe that there is not only a need for an opioid strong enough to alleviate such pain but opioids have the potential to be more beneficial than harmful when controlled and monitored appropriately.[[7]] DSUVIATM is targeted at a population where opioid analgesic treatment is required but i.v. administration is not feasible and oral delivery is impractical (e.g., patient can’t swallow).[[8]] Additionally it is argued that the dissolving sublingual tablet is superior to current methods of opioid delivery because the absorption is prolonged resulting in longer analgesia treatment.[8] The Department of Defense (DOD) provided funding support for DSUVIATM with the primary interest of aiding U.S. soldiers wounded in battle. Scott Gottlieb, commissioner of the FDA from 2010 to 2019, supported the approval stating on Twitter that “[w]hile DSUVIATM brings another highly-potent opioid to market it fulfills a limited, unmet medical need.” The unmet need refers to soldiers who often do not have access to intravenous treatment on the battlefield, making an equally potent tablet form necessary for the initial treatment of battlefield injuries.

The indications and usage of DSUVIATM, however, do not explicitly limit use to the soldier population. Like most drugs, it will be left to the discretion of the medical professionals administering the drug, thus increasing the population of patients that may be exposed to such a potent opioid. Critics question whether the FDA should have approved such a drug in the current climate of opioid abuse striking our nation. Dr. Raeford E. Brown, chair of the FDA’s Advisory Committee on Analgesic Drug Products, expressed his concerns in a statement to the FDA arguing that over the past 10 years there has been no historical proof of successful control over any of the marketed opioids nor sufficient data demonstrating their safety.[3]

Scott Gottlieb addressed the controversy around the new opioid approval by explaining that the FDA approves drugs when the benefits outweigh the risks and when there is sufficient evidence for the safety and efficacy for use of the drug in humans.[1] Table 1 lists a brief comparison between the different views (critics vs. advocates) for DSUVIATM.

Table 1. Comparison of views presented by critics and advocates of DSUVIATM.

Topic Critics of DSUVIATM Advocates for DSUVIATM
Method of delivery ·         Increases likelihood of illicit diversion (small pill)

·         Abuse by healthcare individuals is not uncommon

·         Improves dosing control

·         Noninvasive

·         Brings treatment for unmet population of patients unable to take i.v. and oral tablet

Pharmacological potency

(API – sufentanil)

·         1,000 times more potent than morphine

·         Highly addictive

·         Irrelevant because API is currently used intravenously in hospital settings
Opioid crisis and health of the general population ·         Approval increases the risk of abuse, addiction, and misuse (e.g., fentanyl is produced illicitly and contributes to many deaths)

·         No historical proof of FDAs ability to enforce control

·         No post-marketing assessment

·         REMS program for opioids

·         Specific regulation defined for use of DSUVIATM to prevent risks (e.g., only available in hospital setting making accessibility to the general public limited)

·         Usage has limit of 72 hours maximum


Meets an unmet need ·         Benefits don’t outweigh the risk, when potent opioids are already on the market ·         Provides management of extreme pain (e.g., soldiers)

·         Years since any new opioid has been brought to the market


There has also been talk about AcelRx Pharmaceuticals (the company that developed and commercialized DSUVIATM in the United States) looking for a Canadian partner to obtain approval for the opioid through Health Canada.[[9]] This is alarming considering Canada’s opioid crisis is also on the rise. The Canadian government is specifically concerned with the harm caused by opioids, including fentanyl, and have taken federal action to control opioid substance abuse.[[10]] A number of medical professionals are urging Health Canada to carefully consider such an approval as it brings a large risk to the general public.[9]

In summary, the FDA approved a new form of a potent analgesic opioid for a population of adults requiring strong medication to relieve pain. The question as to whether placing another opioid on the market was necessary is surrounded by a strong controversy. The main concerns are (1) whether the needs of those with acute uncontrolled pain who will benefit from the medication are outweighed by the government’s responsibility to protect the society as a whole and (2) is the REMS for DSUVIATM (or any opioid/drug) adequate to address the potential risks of abuse.


L’Approbation d’un nouvel Opioïde (DSUVIATM) par la FDA qui fait controverse – Est-ce que c’est nécessaire?  

Par Dieanira Erudaitius, Ph.D., Scientifique à Cato Research

Le 02 novembre 2018, l’Agence Américaine des Produits Alimentaires et Médicamenteux (ci-après FDA) aux États-Unis a approuvé l’analgésique opioïde DSUVIATM.[[11]] L’utilisation prévue de ce médicament est réservée aux adultes pour lesquels aucun traitement pour la douleur aiguë, autre que les opiacés, n’est disponible.

DSUVIATM est un comprimé sublingual contenant l’ingrédient pharmaceutique actif sufentanil, une substance contrôlée inscrite à l’annexe II de la United States Controlled Substances Act.[[12]] Sufentanil est un analogue de fentanyl; mais contrairement au fentanyl, qui est 100 fois plus puissant que la morphine, sufentanil est 1,000 fois plus puissant.[[13]] Cela soulève d’importantes inquiétudes concernant des problèmes d’abus et de dépendance. Malgré cela, les promoteurs signalent que le sufentanil est déjà utilisé dans le contexte hospitalier avec la distinction que la drogue est administrée par voie intraveineuse. En effet, l’administration intraveineuse des opioïdes peut fournir un soulagement immédiat aux patients, mais aussi augmenter les risques de surdosage.[[14]] DSUVIATM étant administré par voie sublinguale [[15]], les partisans affirment qu’il est plus facile de contrôler le dosage.

Sans égard à leur puissance, les opioïdes peuvent poser de graves problèmes de santé aux patients à cause des risques associés à la dépendance, l’abus, et l’usage inadéquat de la drogue. Les opposants à l’approbation de DSUVIATM informent aussi que la petite taille du comprimé facilite le détournement illicite ce qui n’est pas inhabituel et constitue un grave problème pour cette classe d’agent pharmacologique.[3] La FDA n’a pas la capacité de contrôler ou prévenir ce type d’abus, mais ils ont imposé des conditions d’utilisation strictes. Par conséquent, un programme complémentaire sous le nom « Stratégie d’évaluation et d’atténuation des risques » (REMS, son acronyme en anglais) a été mis en place pour garantir que les risques d’exposition accidentelle sont limités.[[16]] En outre, DSUVIATM at été approuvé uniquement pour l’usage dans les centres médicaux supervisés, ce qui comprend les salles d’urgence, les hôpitaux, et les centres de chirurgie où un professionnel de la santé doit administrer la drogue.[2]

De nombreux experts médicaux et de partisans d’un contrôle plus stricte des opioïdes questionnent la nécessité d‘un autre opioïde sur le marché. Un argument couramment invoqué pour justifier le besoin d’une opioïde puissante est celui de l’  « oligoanalgesia » (le traitement inadéquat de la douleur) qui demeure une priorité des services de santé, notamment pour les patients admis aux urgences. Les promoteurs suggèrent qu’il existe toujours un besoin pour des opioïdes suffisamment fort pour soulager adéquatement la douleur et que les opioïdes peuvent présenter l’avantage d’être plus bénéfiques que néfastes quand ils sont rigoureusement contrôlés et surveillés.[[17]] DSUVIATM est destinée aux patients qui nécessitent une analgésie opioïde mais pour lesquels une administration intraveineuse ou orale n’est pas possible (par exemple, un patient n’arrivant pas à avaler).[[18]] De plus, on fait valoir que la formulation en comprimé sublingual à dissolution rapide de DSUVIATM rend ce produit supérieur à d’autres méthodes d’administration puisque que son absorption prolongée entraine également une analgésie prolongée.[8] Le Département de la Défense a fourni un financement pour appuyer le développement de cette drogue afin d’aider les soldats blessés. Scott Gottlieb, commissaire de la FDA de 2010 à 2019, a plaidé en faveur de l’approbation de DSUVIATM. Il a déclaré sur son compte Twitter qu’ « Alors que DSUVIATM apporte un autre opioïde extrêmement puissant sur le marché, il répond à un besoin médical insatisfait » Ce besoin médical insatisfait concerne le traitement des soldats qui souvent n’ont pas accès au traitement intraveineux. Il est donc nécessaire d’avoir une drogue sous forme de comprimés qui est aussi puissante afin de donner les premiers soins aux soldats sur un champ de bataille.

Cependant, l’indication de DSUVIATM n’est pas expressément limitée aux soldats. Comme pour la plupart des médicaments, la décision de prescrire ce nouvel opioïde, et d’ainsi accroitre la population exposée à un produit particulièrement puissant, demeure à la discrétion du médecin traitant. Les critiques questionnent la décision de la FDA d’approuver un tel médicament dans un climat marqué par les problèmes liés à la dépendance et abus d’opioïdes. Dr. Raeford E. Brown, président du comité consultatif sur les analgésiques de la FDA, a exprimé ses préoccupations dans une déclaration à la FDA dans laquelle il souligne qu’au cours de la dernière décennie, il n’y a aucune démonstration qu’un contrôle adéquat n’ait été exercé sur les opioïdes disponibles sur le marché ou qu’il existe suffisamment de données pour démontrer la sécurité de ces produits.[3]

Scott Gottlieb a répondu à la controverse entourant l’approbation de ce nouvel opioïde en expliquant que la FDA approuve les médicaments si les avantages surpassent les risques et s’il existe des éléments de preuve suffisants pour soutenir l’utilisation, la sécurité, et l’efficacité de la drogue.[1] Une brève comparaison entre les points de vue exprimés par ces deux positions (partisans et détracteurs) est fournie dans le Tableau 1.

Tableau 1. Comparaison entre les deux groups.

Sujet Les Critiques de DSUVIATM Les Promoteurs de DSUVIATM
Le mode d’administration ·         Accroît la probabilité de détournements illicites (une petite pilule)

·         L’abus par les professionnels de la santé n’est pas rare

·         La précision de dosage s’améliorera

·         Non invasive

·         Il offre de traitements aux patients qui sont incapable d’avaler un comprimé et administration intraveineuse n’est pas une solution

La puissance pharmacologique (ingrédient pharmaceutique actif – sufentanil) ·         1,000 fois plus puissant que la morphine

·         Il crée une forte dépendance

·         Non pertinent parce que l’ingrédient pharmaceutique actif est actuellement utilisé à l’hôpital par voie intraveineuse
L’abus d’opioïdes et la santé de la population en général ·         L’approbation augmente considérablement les risques entourant l’abus, d’accoutumance, et de mésusage (par exemple fentanyl est illicitement produite et il contribue aussi à de nombreux décès)

·         Il n’y a aucune preuve historique démontrant la capacité de la FDA à assurer le contrôle

·         Pas d’évaluation postcommercialisation

·         Programme REMS pour des opioïdes

·         L’utilisation de DSUVIATM est restreinte à des instructions strictes afin de réduire les risques (par exemple, offert exclusivement en milieu hospitalier limitant ainsi l’accès au grand public)

·         L’utilisation de DSUVIATM est limitée à une période de 72 heures

Combler un besoin non satisfait ·         Les bénéfices ne sont pas supérieurs aux risques puisque d’autre opioïdes existent déjà sur le marché ·         Fournir une gestion de la douleur extrême (par exemple pour les soldats)

·         Plusieurs années depuis qu’un nouvel opioïde a été mis sur le marché


Il a également été rapporté qu’AcelRx Pharmaceuticals (l’entreprise qui a développé et commercialisé DSUVIATM aux États-Unis) est à la recherche d’un partenaire Canadien pour obtenir l’approbation de DSUVIATM par Santé Canada.[[19]] Ceci pourrait être encore plus alarmant pour certains si l’opioïde est approuvé, compte tenu de la crise des opioïdes qui se fait également sentir au Canada. Le gouvernement canadien s’intéresse particulièrement aux dommages causés par les opioïdes, notamment le fentanyl, et le gouvernement fédéral a pris des mesures pour contrôler l’abus de cette substance à l’échelle nationale.[[20]] De nombreux professionnels de la santé incitent Santé Canada à considérer l’approbation de ce médicament avec précaution à cause des risques à la santé publique.[9]

En résumé, la FDA a approuvé un opioïde puissant sous forme de comprimés pour usage chez l’adulte qui a besoin de médicaments analgésiques pour la douleur. La question de savoir si ajouter un autre opioïde sur le marché est absolument nécessaire a suscité une discussion. Les considérations majeures sont: (1) Est-ce que les besoins du patient qui souffre de douleurs violentes dépassent la responsabilité du gouvernement à protéger la société entière et (2) Est-ce que le programme REMS pour DSUVIATM sera adéquat pour faire face aux risques potentiels d’abus?


[[1]] “Statement from FDA Commissioner Scott Gottlieb, M.D., on agency’s approval of Dsuvia and the FDA’s future consideration of new opioids”. The U.S. Food & Drug Administration. 02 November 2018.

[[2]] “Full Prescribing Information for Dsuvia” (2018) AcelRx Pharmaceutical, Inc.

[[3]] “For a Public Hearing on Fentanyl and Synthetic Cannabinoids” Statement by Tell, S.R. before the U.S. Sentencing Commission. 05 December 2017.

[[4]] Patanwala, A. E., Keim, S. M., and Erstad, B. L. (2010). Intravenous opioids for severe acute pain in the emergency department. Annals of Pharmacotherapy44(11), 1800-1809.

[[5]] “Dsuvia Direction for Use” (2018) AcelRx Pharmaceutical, Inc.

[[6]] “Approved Risk Evaluation and Mitigation Strategies (REMS)”. The U.S. Food & Drug Administration. 02 November 2018.

[[7]] Motov and Khan (2009). Problems and barriers of pain management in the emergency department: Are we ever going to get better? Journal of Pain Research. 2: 5-11.

[[8]]  “Meeting of the anesthetic and analgesic drug products advisory committee”.  FDA Advisory Committee Briefing Document. 12 October 2018.

[[9]] “Canadian doctors urge caution after FDA approves controversial new opioid pill” CBC News. 07 November 2018.

[[10]] “Responding to Canada’s opioid crisis”. Government of Canada. 18 December 2018.

[[11]] “Statement from FDA Commissioner Scott Gottlieb, M.D., on agency’s approval of Dsuvia and the FDA’s future consideration of new opioids”. The U.S. Food & Drug Administration. 02 November 2018.

[[12]] “Full Prescribing Information for Dsuvia” (2018) AcelRx Pharmaceutical, Inc.

[[13]] “For a Public Hearing on Fentanyl and Synthetic Cannabinoids” Statement by Tell, S.R. before the U.S. Sentencing Commission. 05 December 2017.

[[14]] Patanwala, A. E., Keim, S. M., and Erstad, B. L. (2010). Intravenous opioids for severe acute pain in the emergency department. Annals of Pharmacotherapy44(11), 1800-1809.

[[15]] “Dsuvia Direction for Use” (2018) AcelRx Pharmaceutical, Inc.

[[16]] “Approved Risk Evaluation and Mitigation Strategies (REMS)”. The U.S. Food & Drug Administration. 02 November 2018.

[[17]] Motov and Khan (2009). Problems and barriers of pain management in the emergency department: Are we ever going to get better? Journal of Pain Research. 2: 5-11.

[[18]] “Meeting of the anesthetic and analgesic drug products advisory committee”.  FDA Advisory Committee Briefing Document. 12 October 2018.

[[19]] “Canadian doctors urge caution after FDA approves controversial new opioid pill” CBC News. 07 November 2018.

[[20]] “Responding to Canada’s opioid crisis”. Government of Canada. 18 December 2018.

Mar 18

New FDA Guidances for February 2019

By Joanne McNelis, Ph.D., RAC (US), Scientist II at Cato Research

FDA draft and final guidances released from CDER, CBER, and CDRH in December are posted. In addition, upcoming advisory committee meetings are listed below with links to more information.


Special Interest Guidances/Information Date Posted
Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act Guidance for Industry – Final Guidance 28 Feb 2019
Quality Considerations for Continuous Manufacturing Guidance for Industry – Draft Guidance 26 Feb 2019
Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology Considerations – Draft Guidance 25 Feb 2019
Bioavailability Studies Submitted in NDAs or INDs – General Considerations – Draft Guidance 25 Feb 2019
Acceptance and Filing Reviews for Premarket Approval Applications (PMAs) – Guidance for Industry and Food and Drug Administration Staff – Final Guidance 25 Feb 2019
Refuse to Accept Policy for 510(k)s – Guidance for Industry and Food and Drug Administration Staff – Final Guidance 25 Feb 2019
Implanted Brain-Computer Interface (BCI) Devices for Patients with Paralysis or Amputation – Non-clinical Testing and Clinical Considerations – Draft Guidance for Industry and Food and Drug Administration Staff – Draft Guidance 25 Feb 2019
Smoking Cessation and Related Indications: Developing Nicotine Replacement Therapy Drug Products Guidance for Industry – Draft Guidance 21 Feb 2019
Expedited Programs for Regenerative Medicine Therapies for Serious Conditions; Guidance for Industry – Final Guidance 19 Feb 2019
Evaluation of Devices Used with Regenerative Medicine Advanced Therapies; Guidance for Industry – Final Guidance 19 Feb 2019
Nonbinding Feedback After Certain Food and Drug Administration Inspections of Device Establishments – Draft Guidance for Industry and Food and Drug Administration Staff – Draft Guidance 19 Feb 2019
Competitive Generic Therapies Guidance for Industry – Draft Guidance 15 Feb 2019
CDER’s Program for the Recognition of Voluntary Consensus Standards Related to Pharmaceutical Quality – Draft Guidance 13 Feb 2019
Intent to Exempt Certain Unclassified Medical Devices from Premarket Notification Requirements – Guidance for Industry and Food and Drug Administration Staff – Final Guidance 08 Feb 2019
Principles of Premarket Pathways for Combination Products – Draft Guidance 06 Feb 2019
Opioid Use Disorder: Developing Depot Buprenorphine Products for Treatment – Final Guidance 06 Feb 2019
The Least Burdensome Provisions: Concept and Principles – Guidance for Industry and FDA Staff – Final Guidance 05 Feb 2019
Upcoming Meetings (* = New)
* March 19-20, 2019: Science Advisory Board to the National Center for Toxicological Research Meeting Announcement
* March 20-21, 2019: Blood Products Advisory Committee Meeting Announcement
March 21, 2019: Neurological Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* March 25-26, 2019: General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
March 27, 2019: Meeting of the Pulmonary-Allergy Drugs Advisory Committee Meeting Announcement
Last updated: 07 March 2019

Mar 12

Lets talk about Patient Engagement

Why does everyone talk about “Patient Engagement” in clinical trials?

By Shirley Greenfeld

Senior Clinical Research Associate

As trials are becoming longer and more expensive and many of them fail to meet their recruitment goal, patient engagement plays a key role in the success of a clinical trial. But what is exactly patient engagement and why is it so important?

Getting to know the person behind the “subject” title

Times have changed, and nowadays, more than ever before, patients are more involved in their own clinical care. Equipped with knowledge gained from a variety of available resources, they bring their own views coupled with high expectations regarding their treatment options.

There is an increasingly growing understanding that it’s important to pay much more attention to our main stakeholder – the patient. Patients who are experiencing the illness first-hand, are an invaluable resource, capable of clarifying their priorities and true needs. These insights help to better shape the trial’s design and protocol long before you embark on the long path that is R&D. They can provide a unique point of view that will help optimizing the development process, identify knowledge gaps and better shape the protocol and the trial’s endpoints.

patient engagement , clinical trials

Patients can provide information about the things that actually matter to them – the daily burden of the disease, their unmet needs, therapeutic burdens, risk-benefit ratio and more, directing the researcher to ask the correct questions. The way there is clear – by creating a true and meaningful partnership between the patient and the researcher. This partnership can transform the clinical development process from one that is directed by sponsors and investigators to a process driven by the needs of patients and their caregivers.

Current state of affairs

Recent efforts focus on formalizing the partnership process by creating designated models. These are three suggested models:

  • Patients as advisory board members – it consists of a group of patients with similar characteristics to the expected trial population who meet regularly with the clinical staff to help improve performance. They provide their experience and advise on aspects such as eligibility criteria and the follow-up phone call schedule to help researchers design a trial that would be both useful for patients and easy for them to participate in.
  • Patients as steering committee members -The selected individual would give input on protocol design, anticipated burden for study participants, recruitment and retention tactics, and other key areas. The organization who is responsible for the study or the sponsor would also be responsible for the engagement and education of this patient representative, whose views would carry as much weight as those of other steering committee members.
  • Patients as co-investigators – patients and caregivers are includedas co-principal investigators (PI). As a co-PI, they oversee patient engagement efforts and work to address potential barriers to patient involvement by openly discussing concerns about data security and anonymity. They are also in charge of creating a patient- and family-friendly glossary of acronyms commonly used within the medical community.

These efforts are very important as although there are increased levels of patient interest in treatment options, appreciation of clinical trials as a viable care alternative is still limited. The partnership models can offer a patient centric framework and help raise awareness and willingness to participate in clinical trials.

A great example for the significance of patients in the trials design is the CONNECT-HF trial funded by Novartis. It’s a special kind of study, not testing a new medication but trying to understand what kind of care and resources people with HF use after leaving the hospital. The researchers’ goal is collecting information from patients to better understand what kind of support and care is the most helpful during the time they leave the hospital and recover at home. This is a unique study with the potential to open a window for HF patients’ true needs and pains. Those insights can help researchers better define HF trials outcomes and patient centric design.

In this study, the team worked closely with a patient advisory group. The selected group had similar characteristics to the trial group (age, sex, race/ethnicity, and geographical location) but they never participated in a clinical trial. This advisory group offered their experiences and advice on aspects such as eligibility criteria and the follow-up phone call schedule to help researchers design a trial that would be both useful for patients and easy for them to participate in.

Looking ahead

True patient engagement and patient centricity models will need to reflect the factors that drive patients’ decisions to enroll and remain in clinical trials. Protocol design, site selection, site staff training, employed technologies, provided information will all need to be examined through the eyes of the patients and their needs.  The bottom line is that patients find

in-person interactions during the trials as the most effective way to contribute to their engagement. That is why including them in the process is so essential.

The present conception shows that patient engagement activities will increase over the next few years. Considering that patient centricity and patient engagement weren’t given much attention until five or six years ago, we should expect to wait a little while longer to witness a true change. New effective models of engagement are still necessary.

Remembering why we are doing what we are doing

In the end, the purpose of drug development is to help people in need and improve their lives. If we want to perfect our ability in doing so, we need to learn to better tailor our trials to the true needs of the people they are designed for.

If we want to elevate enrollment rates and improve retention, we need to change our perception and start thinking of patients as our most valuable asset. We must emphasize the personal relationship between the patient and the clinical staff alongside the development of mobile and digital technology.


  1. “Models of Engagement: Patients as Partners in Clinical Research” from applied clinical trial. http://www.appliedclinicaltrialsonline.com/models-engagement-patients-partners-clinical-research

  1. http://connectheartfailure.org/about-connect-hf

Mar 05


By Mabel Ruscitti and Arnavaz Eduljee, Cato Research

AWARENESS: Traumatic Brain Injury (TBI) occurs from a blow, jolt, bump or a penetrating object to the head.[1, 2] Traumatic brain injury can lead to brain cell death, inflammation, edema, hemorrhage, and severe disruption to normal brain cell function.  Concussion injury frequently results in persistent functional impairment including problems with cognitive function, memory, mood, and other personality disorders.  Traumatic brain injury is a leading cause of death and disability in industrialized societies, particularly among young people. It is most prevalent in males under 40 and in the elderly. 5.3 million Americans currently live with disabilities related to TBI. The causes of TBI include: falls, blunt trauma, motor vehicle crashes, sports injuries, violence, and explosive blasts from combat.[1] TBI ranges from mild to severe and there are two broad categories: closed and open. Closed TBI include: concussions (most common mild TBI, where patients completely recover), diffuse axonal injury (tearing of brain tissue occurring from sudden acceleration/deceleration such as in shaken baby syndrome and in some bicycle, car or motorcycle accidents), and contusions (bleeding from blows to the head); Open TBI consist of penetration injury from bullets or other objects.[1] Brain injury is a leading cause of combat casualties. In the military, there was a steady increase in the incidence of mild TBI among active U.S. service members between 1997 and 2007; however, the incidence rate has risen significantly over the past few years. This was most marked among those serving in Iraq and Afghanistan, where there was a 38.4% and 15.3% average annual increase in new cases, respectively.[3] Severe TBI is also one of the leading causes of death, with approximately 70% mortality, 50% of affected individuals dying before reaching medical care, and 20% dying after reaching a field hospital.[4]

SYMPTOMS: The symptoms of TBI can appear immediately or increase/decrease over time depending on the individual and type of trauma. Changes to the individual can be so dramatic, that they make it difficult for others to understand these changes.[5] Depending on the severity and part of the brain damaged, TBI can cause alteration of consciousness, impair thinking, decision making and reasoning, problem solving, concentration, memory, balance, movement, and/or sensation, and cause emotional problems (personality changes, impulsivity, anxiety, and depression) and seizures.[6] Brain damage involving frontal or temporal lobes results in poor reasoning and judgment skills, shortened attention span, needing more time to understand information, difficulty learning new things, difficulty beginning tasks, making plans or decisions, organizing, disinhibition, lack of impulse control, inappropriate behavior, angry outbursts, rigid thinking, getting stuck on a subject or activity, inability to empathize with others, slurred speech, difficulty with muscle coordination or balance, fatigue, weakness, insomnia, headaches, and full or partial paralysis.[1, 7, 8] Because of these sequelae, persons with brain injuries face serious employment and social challenges and isolation. Many end up estranged from family and friends due to their behavior,[9] which has become inappropriate, intolerable, and even frightening and dangerous at times.[8] In fact, 60‑80% of inmates have suffered at least one serious brain injury.[10] Because of the lasting impact in their quality of life, TBI survivors are at a high risk of depression,[1, 8] and may develop other mental illnesses such as obsessive compulsive disorder,[8] post-traumatic disorder, and substance abuse.[8] Additionally, they present an elevated suicide rate.[2, 11]

PROCEDURES: The majority of TBI cases seen in emergency rooms are treatable if diagnosed soon enough.[12] CT scans, MRI, neurological and neuropsychological testing (such as Columbia Suicide Severity Rating Scale, Post-Concussion Symptom Scale, Post-Traumatic Stress Disorder Checklist, Sheehan Disability Scale, pupillometry and others) are used in the diagnosis. The Glasgow Coma Scale is used to determine the initial severity of a brain injury, but no test can predict recovery. Survival of severe brain injury victims is dependent on avoiding or minimizing the secondary systemic and intracranial effects as a result of the initial trauma.[13] These secondary effects include hemorrhage, cerebral edema or inflammation, and multiple neurometabolic cascades of biochemical changes that ultimately exacerbate neuronal cell death.[13, 14] Procedures to reduce brain swelling after head injury include the use of mannitol or hypertonic saline.[15, 16] Barbiturates, ventriculostomy, and decompressive craniectomy may serve the same purpose.[16] There is no high-quality evidence that hypothermia is beneficial for severe TBI.[15] After initial acute treatment in the ICU, recovery from TBI may take months to years and involves inpatient rehabilitation by a multidisciplinary team including physicians, nurses, neurologists, neuropsychologists, occupational, physical, speech, and language therapists.[7, 17] After discharge, caregivers should be informed of possible sequelae and proven techniques to help calm down the TBI family member. Ongoing psychotherapy should be implemented, including cognitive behavioral therapy to improve problem-solving skills, self-esteem, and psychosocial functioning following TBI,[18] There are no FDA-approved medications yet for treating neuropsychiatric sequelae of TBI, thus, treatment should be symptom-based and employ the “start low, go slow” approach.[19] Drugs such as Namenda and Aricept might help with memory problems after brain injury.[20, 21] Over time, the patient should build a new identity and life based on his current abilities, interests, and passions.[22] The implementation of an adaptive living environment, home care aid, and a structured routine should be beneficial to the TBI survivor. Currently there are several clinical trials being conducted in TBI patients, some being funded by the Department of Defense in the US.

PREVENTION: Precautions to prevent TBI, include wearing protective helmets in sports and at the workplace (such as construction sites).[2] Drinking and driving should be avoided, and drivers and passengers should always wear lap belts and shoulder harnesses; child safety seats should be properly installed. To help prevent falls at home, there should be adequate lighting and no obstacles in walking pathways, and hand rails should be used on stairways and for the elderly, in the bathroom. Adequate shoe ware should be worn, and ice grippers should be used under icy weather.



  1. Family Caregiver Alliance webpage. Traumatic Brain Injury. 2019; Available at: https://www.caregiver.org/traumatic-brain-injury; Accessed February 28, 2019.
  2. HealthDay website. When Head Injuries Make Life Too Hard, Suicide Risk May Rise. 2019; Available at: https://consumer.healthday.com/cognitive-health-information-26/traumatic-brain-injury-1002/when-head-injuries-make-life-too-hard-suicide-risk-may-rise-736720.html; Accessed February 28, 2019.
  3. Cameron KL, Marshall SW, Sturdivant RX, Lincoln AE. Trends in the incidence of physician-diagnosed mild traumatic brain injury among active duty U.S. military personnel between 1997 and 2007. J Neurotrauma 2012;29(7):1313-1321.
  4. Sapsford W. Penetrating brain injury in military conflict: does it merit more research? J R Army Med Corps 2003;149(1):5-14.
  5. Brain Injury Association of America website. Adults: What to Expect at Home. @biaamerica, 2019; Available at: https://www.biausa.org/brain-injury/about-brain-injury/adults-what-to-expect/adults-what-to-expect-at-home.
  6. National Institute of Neurological Disorders and Stroke website. Traumatic Brain Injury: Hope Through Research. 2019; Available at: https://www.ncbi.nlm.nih.gov/pubmed/; Accessed February 28, 2019.
  7. Family Caregiver Alliance webpage. Coping with Behavior Problems after Head Injury. 2019; Available at: https://www.caregiver.org/coping-behavior-problems-after-head-injury; Accessed February 28, 2019.
  8. PsychToday. After Brain Injury: The Dark Side of Personality Change Part I. @PsychToday, 2019; Available at: http://www.psychologytoday.com/blog/professor-cromer-learns-read/201203/after-brain-injury-the-dark-side-personality-change-part-i; Accessed February 28, 2019.
  9. Brainline website. Loss of Relationships After a TBI Is Often the Most Devastating Outcome. 2012; Available at: https://www.brainline.org/video/loss-relationships-after-tbi-often-most-devastating-outcome; Accessed February 28, 2019, 2012-07-30.
  10. Northern Brain Injury Association website. Welcome to the Northern Brain Injury Association. 2019; Available at: http://nbia.ca/; Accessed February 28, 2019.
  11. Hudak A, Warner M, de la Plata CM, Moore C, Harper C, Diaz-Arrastia R. Brain morphometry changes and depressive symptoms after traumatic brain injury. Psychiatry Res 2011;191(3):160-165.
  12. Brain Injury Canada website. Prevention and Treatment. 2019; Available at: https://www.braininjurycanada.ca/acquired-brain-injury/prevention-and-treatment/; Accessed February 28, 2019.
  13. Case Western Reserve University School of Medicine web site. Primary vs. Secondary Insults in Traumatic Brain Injury. 2019; Available at: http://casemed.case.edu/clerkships/neurology/NeurLrngObjectives/TBI%20primary%20vs%20secondary.htm; Accessed February 28, 2019.
  14. Morganti-Kossmann C, Semple B, Ziebell J, Yan E, Bye N, Kossmann T. 10 – Modulation of Immune Response by Head Injury. In: New Insights to Neuroimmune Biology. Elsevier ed.   2010:193-220.
  15. Cochrane website. Mannitol for acute traumatic brain injury. 2019; Available at: https://www.cochrane.org/CD001049/INJ_mannitol-for-acute-traumatic-brain-injury; Accessed February 28, 2019.
  16. McBride DW, Szu JI, Hale C, Hsu MS, Rodgers VG, Binder DK. Reduction of Cerebral Edema after Traumatic Brain Injury Using an Osmotic Transport Device. In: J Neurotrauma. Vol 31,   2014:1948-54.
  17. Model Systems Knowledge Translation Center (MSKTC) website. Traumatic Brain Injury and Acute Inpatient Rehabilitation | Model Systems Knowledge Translation Center (MSKTC). 2019; Available at: https://msktc.org/tbi/factsheets/traumatic-brain-injury-and-acute-inpatient-rehabilitation; Accessed February 28, 2019.
  18. Jorge RE, Arciniegas DB. Mood Disorders after TBI. Psychiatr Clin North Am 2014;37(1):13-29.
  19. Scher LM. Traumatic brain injury: Pharmacotherapy options for cognitive deficits. Current Psychiatry 2011;10(2):21-37.
  20. Brainline website. Can the Drugs Namenda and Aricept Help After Brain Injury? 2014; Available at: https://www.brainline.org/qa/can-drugs-namenda-and-aricept-help-after-brain-injury; Accessed February 28, 2019, 2014-09-10.
  21. Cochrane website. Pharmacotherapy for chronic cognitive impairment in traumatic brain injury – Dougall, D – 2015 | Cochrane Library. 2015; Available at: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD009221.pub2/full; Accessed February 28, 2019.
  22. PsychToday. After Brain Injury: The Dark Side of Personality Change Part 2. @PsychToday, 2019; Available at: http://www.psychologytoday.com/blog/professor-cromer-learns-read/201203/after-brain-injury-the-dark-side-personality-change-part-2; Accessed February 28, 2019.


Feb 28

Revised FDA Guidance on Developing Rare Disease Therapies

by Kristen Biernat, Ph.D., Scientist at Cato Research


Rare diseases, defined as conditions affecting fewer than 200,000 people in the United States, pose a significant health care concern.1 There are approximately 7,000 rare diseases that cumulatively affect more than 25 million Americans, half of which are children.2 In addition, most rare diseases are serious or life-threatening disorders with unmet medical needs.

Due to the small patient populations and complexity of rare diseases, many sponsors were previously reluctant to develop treatments for these conditions. However, this changed with the passage of the Orphan Drug Act (ODA) of 1983, which offers sponsors incentives, such as the waiver of user fees and a 7-year market exclusivity period, to make drug development for rare diseases financially viable.1 The ODA resulted in a significant increase in the number of approvals of rare disease therapies, with more than 750 orphan drug products approved since the enactment of the ODA and 90 products approved in 2018 alone.3

Despite the dramatic increase in the number of approvals, sponsors continue to face challenges when developing therapeutics for rare diseases. These challenges stem from an incomplete understanding of the natural history and pathophysiology of the disease, the limited number of patients available for clinical trials, and the pediatric populations that are often affected.

To address these issues, the Food and Drug Administration (FDA) released a draft guidance in 2015, Rare Diseases: Common Issues in Drug Development, which aimed to assist sponsors in conducting more efficient and successful drug development programs for rare diseases. On 16 January 2019, the FDA issued an update to its 2015 guidance. The revisions include the following:

  1. An updated Natural History Studies section

The FDA highlights the importance of evaluating natural history knowledge early to inform drug development programs. Because the natural history of rare diseases is often limited, conducting natural history studies can provide a sponsor with a greater understanding of the disease and aid in defining the disease population, selecting clinical endpoints, or identifying new biomarkers.

According to the guidance, natural history study designs can be characterized as (1) retrospective or prospective and (2) cross-sectional or longitudinal, with each study type possessing advantages and disadvantages. It is important to carefully evaluate these during drug development planning stages as a natural history study may also be used as an external control group for interventional trials.

  1. Inclusion of issues for surrogate biomarkers

Because the knowledge about a rare disease’s pathophysiology and clinical manifestations is often incomplete, efficacy endpoints are not always available. This guidance indicates that sponsors can use biomarkers as surrogate endpoints in some cases. However, the use of a surrogate endpoint requires demonstration of analytical and clinical validation of the biomarker test, and analytical validity should be confirmed before starting the clinical trial.

  1. Nonclinical flexibility

Regulations state that the FDA may exercise flexibility in applying regulatory standards for drugs that treat serious and life-threatening diseases, as long as safety and effectiveness are preserved. When determining nonclinical flexibility, the FDA evaluates several factors, including the pharmacological and chemical characteristics of the drug, the design and objectives of the proposed clinical investigations, the anticipated risks to humans, and the existing accumulated nonclinical toxicology and human data.

  1. Additional information on external controls and early randomization

For rare diseases with an unmet medical need, a single-arm trial, in which all enrolled patients receive the investigational drug, with an external control may be used when there is a highly predictable disease course and a large, self-evident expected drug effect. However, randomized, controlled trials are often the most efficient way to determine the clinical effect of a drug. When a randomized trial is feasible, randomization should also be carried out as early as possible. Importantly, sponsors should address any concerns about control arms with patients and other stakeholder groups early to avoid undermining trial recruitment and retention.

  1. Addition of a Safety section

To evaluate safety, the sponsor should characterize the drug’s safety profile in a reasonable number of patients over a reasonable duration of time. For rare diseases, the term reasonable must take into account certain feasibility challenges, including the limited number of patients with the disease and the patients’ tolerance for risk in an unmet medical need setting. For example, a smaller number of patients may be acceptable when the intended treatment population is small.

  1. Additional information on changes to drug substance or manufacturing process

The FDA may also exercise flexibility on the manufacturing information needed for submission. When determining manufacturing flexibility, the FDA will consider factors such as product characteristics, seriousness of the condition and medical need, manufacturing processes, the robustness of the sponsor’s quality system, and the strength of the sponsor’s risk-based quality assessment.

  1. Inclusion of an Additional Considerations section

Information on patient participation, expedited programs, and pediatric considerations is also included in the revised guidance. The FDA encourages the participation of patients, caregivers, and advocates in rare disease drug development programs because their perspectives and experiences may provide meaningful information for the drug review process.  Because most rare diseases are serious or life-threatening with unmet medical needs, the FDA also encourages sponsors to consider fast track designation, breakthrough therapy designation, priority review, and accelerated approval for their drug development programs. Finally, given that about half of the people affected by rare diseases are children, the FDA strongly encourages sponsors to study the drug in all relevant pediatric populations so that it may be labeled for pediatric use.



1Public Law 97-414, 96 Stat. 2049 (1983). Amended by Public Law 98-551 (1984) to add a numeric prevalence threshold to the definition of rare diseases.

2NIH National Center for Advancing Translational Sciences. Genetic and Rare Disease Information Center. FAQs about Rare Diseases. Updated 30 Nov 2017. Available from: https://rarediseases.info.nih.gov/diseases/pages/31/faqs-aboutrare-diseases

3FDA. Search Orphan Drug Designations and Approvals. 28 Jan 2019. Available from: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

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Feb 19

Pharmacogenetics- Tailoring your product to fit the genes

Pharmacogenetics – Tailoring your product to fit the genes

By Carron Sher, M.D.

Senior Clinical Research Physician


John received anti-malarial therapy and developed severe hemolytic anemia.  He was diagnosed as having G6PD deficiency. Sally was started on warfarin and there was a problem in achieving the desired therapeutic response.  She was diagnosed as having the CYP2C9 *2 variant.

In John’s case a genetic variant resulted in a potentially life-threatening adverse event while in Sally’s case a genetic variant resulted in requiring a lower dose of the drug.

Just as one pair of jeans does not fit all so one drug does not fit all and part of the reason is genetic variation.

The idea behind pharmacogenetics — that a person’s genes influence their responses to medicinal drugs — is not new1.  The history of pharmacogenetics stretches as far back as 510 b.c. when Pythagoras noted that ingestion of fava beans resulted in a potentially fatal reaction in some, but not all, individuals2.

Pharmacogenetic variation (eg. in acetylation, hydrolysis, oxidation, or drug-metabolizing enzymes) can have clinical consequences. For example, if patients metabolize certain drugs rapidly, they may require higher, more frequent doses to achieve therapeutic concentrations; if patients metabolize certain drugs slowly, they may need lower, less frequent doses to avoid toxicity, particularly of drugs with a narrow margin of safety3.

In short, some genetic variants make drugs toxic for some; others render certain drugs ineffective1.

Pharmacogenetics has become one of the leading and potentially most actionable areas of personalized medicine, as evidenced by the increased availability of clinical pharmacogenetic testing among CLIA-approved laboratories over the past few years4. Currently, variations in around 20 genes provide useful predictions of reactions to 80–100 drugs — about 7% of drugs approved by the US Food and Drug Administration1,3.

Guidelines have been developed by the NIH-funded Clinical Pharmacogenetics Implementation Consortium (CPIC) to assist physicians in dealing with the results.  This is an international group of pharmacogenetics experts who have so far produced detailed practical advice on 33 drug–gene pairs5.

In practice, however, only a handful of specific tests are routinely used in the clinic today. An example is the antiretroviral agent abacavir, which is prescribed to people who have HIV. Up to 10% of Caucasians carry a particular version of an immune-system gene called HLA-B that gives them a 50% chance of experiencing a life-threatening hypersensitivity reaction to abacavir. Within a few years of the risk allele being identified in 2002, clinics started screening for it before commencing antiretroviral therapy, offering alternative medicines to those with the problematic variant. This decreased the incidence of hypersensitivity, and HLA-B screening is now standard care for HIV patients1.

In an effort to enable further evidence of clinical utility in the post-market period, the FDA Amendments Act of 2007 allows for systematic, ongoing efforts to continue developing evidence for safety and effectiveness after drug approval. Drug product labeling has also been revised after approval to include pharmacogenetic information that can alter the benefit/risk relationship, or allow dosing of the medicine to be adjusted for individuals6.

It is hoped that full ascertainment of genomic information on all subjects during early development will allow early discovery of clinically important genomic differences. As a result, the Food and Drug Administration (FDA) released a “Guidance for Industry Clinical Pharmacogenomics: Premarketing Evaluation in Early Phase Clinical Studies.” The purpose of the guidance is to suggest approaches to improve the quality of the data collected and the ability to assess genomic relationships. The guidance is also intended to assist the pharmaceutical industry and other investigators engaged in new drug development in evaluating how variations in the human genome could affect the clinical pharmacology and clinical responses of drugs. The guidance provides recommendations on when genomic information should be considered to address questions arising during drug development, and in some cases, during regulatory review6,7. Also, ICH E15 provides an agreement on definitions to facilitate the integration of pharmacogenetics into the global drug development and approval process8.

So please remember the genes early on in your drug development program.


  1. Pharmacogenetics: The right drug for you.  Nature 537, S60-62. 2016
  2. Pharmacogenetics and pharmacogenomics. Br J Clin Pharmacol. 52 (4):345-347.  2001
  3. https://www.msdmanuals.com/professional/clinical-pharmacology/factors-affecting-response-to-drugs/pharmacogenetics
  4. Personalizing medicine with clinical pharmacogenetics. Genet Med. 13(12): 987–995. 2011
  5. https://cpicpgx.org/guidelines
  6. https://www.policymed.com/2011/04/fda-guidance-for-industry-clinical-pharmacogenomics-premarketing-evaluation-in-early-phase-clinical-studies.html
  7. Guidance for Industry Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM337169.pdf
  8. Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample coding catgegories. https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E15/Step4/E15_Guideline.pdf

Feb 15

Draft Guidance of the Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA Products

By: Juliati Rahajeng, Ph.D., Clinical Strategy Scientist at Cato Research, and Dieanira Erudaitius, Ph.D., Scientist at Cato Research


A draft guidance with regards to the formal meetings between the FDA and sponsors or applicants of biosimilar or interchangeable products regulated under the Biosimilar User Fee Act (BsUFA) was published in June 2018. It describes the good meeting management practices (GMMPs) and the standardized procedures for requesting, preparing, scheduling, conducting, and documenting such formal meetings.


Types of Meetings

Various types of formal meetings occur between applicants or sponsors and the FDA to discuss development and review of a biosimilar or interchangeable product (as summarized in
Table 1). The type of requested meeting will depend on the stage of development of the biosimilar or interchangeable product and on the type advice being sought. Typically, a sponsor is granted one Biosimilar Initial Advisory (BIA) meeting and one Biosimilar Biological Product Development (BPD) Type 4 meeting for a single biosimilar or interchangeable product. However, a sponsor may request as many BPD Type 2 and Type 3 meetings as needed. These meetings can take place as face-to-face, teleconference or videoconference, and written response only (WRO) formats of communication. WRO meetings can only be requested for BIA and BPD Type 2 meetings.

Table 1           Formal Meeting Types between the FDA and Sponsor of BSuFA Products

Name of Meeting Objective Details of Meeting Type
Biosimilar Initial Advisory meeting To discuss whether licensure under Section 351(k) of the PHS Act may be feasible for a particular product ·         Meeting package should include:

(a) preliminary comparative analytical similarity data from a particular biosimilar or interchangeable product compared to the reference product

(b) an overview of the development program with the synopses of all completed, ongoing, and future studies

·         This meeting type is not for discussions involving significant review of summary data or full study reports

BPD Type 1 To discuss how to address a stalled development program or an important safety issue ·         Examples of topics to discuss include:

(a)    Input on how to address the hold issues should be seek from the FDA when a clinical hold is in place.

(b)   A new path forward needs to be discussed when the applicant has submitted the response to clinical hold issues and the response has been reviewed by the FDA but both the FDA and the sponsor agree that the development is stalled.

(c)    Input on how to address issues from the FDA upon receipt of an FDA nonagreement Special Protocol Assessment letter

(d)   Important safety issues

(e)    Dispute resolutions as described in 21 CFR 10.75 and 312.48

BPD Type 2 To discuss a specific issue so that FDA will provide advice with regards to an ongoing development program ·         Meeting package may include significant review of summary data, but does not include full review of study reports
BPD Type 3 To discuss an ongoing development program ·         This meeting type includes full review of study reports or in-depth data review

·         FDA advice with regards to the similarity between a particular biosimilar of interchangeable product and the reference product

·         FDA advice with regards to the need for additional studies including their design and analysis

BPD Type 4 To discuss content and format of a complete application or supplement submitted under Section 351(k) of the PHS Act ·         A pre-submission meeting for a biosimilar or interchangeable product application

BPD = Biological Product Development; BSuFA = Biosimilar User Fee Act; CFR = Code Federal Regulation; PHS = Public Health Service Act


Planning an Effective Meeting

To have an effective meeting with the FDA, adequate information should be included in the meeting request. Sponsors or meeting requesters are encouraged to consult the information that are publicly made available by the FDA with regards to biosimilar or interchangeable product development and other relevant FDA guidance when planning, developing, and providing information needed to support a meeting with the FDA. Deviations of a product development plan from the current practices or guidance should be recognized and explained. In the meeting package, sponsors or requesters should define the specific areas of input needed from the FDA, which include the objectives of the meeting, the meeting agenda, list of questions for the FDA, list of attendees representing the sponsors, and list of FDA attendees.


Where to Submit Materials

A sponsor has to submit a written meeting request to the FDA through paper submission or via the electronic gateway, as applicable. Meeting requests should be directed to the appropriate review division or office. If previously assigned, a meeting request should be submitted to the pre-investigational new drug file (pre-IND) file or application. A meeting request for the development of a biosimilar or interchangeable product with multiple indications that requires multiple division reviews, should be addressed to the division that has the regulatory oversight of the reference product. The Center for Drug Evaluation and Research (CDER) prefers for copies of the meeting packages to be submitted in electronic and paper format, whereas the Center for Biologics Evaluation and Research (CBER) prefers for copies of the meeting packages to be submitted only in electronic format.


What to Expect After Submitting a Meeting Request to the FDA

Upon receiving a meeting request, the FDA assesses each request and determines whether or not the request will be granted. The FDA will specify the meeting type and format of communication. The FDA will notify the sponsor or requester in writing the decision for the requested meeting within 14 days of BDP Type 1 meeting or 21 days for BIA and BDP Types 2, 3, and 4 meetings. Notification from the FDA usually includes the date, time, conferencing arrangements or location of the meeting, and the expected FDA attendees for the face-to-face and the teleconference or videoconference meetings.

For WRO meeting requests, BIA and BDP Types 1, 2, 3, and 4 meetings are scheduled within 75 days, 30 days, 90 days, 120 days, or 60 days, respectively, from receipt of WRO meeting package. For BIA and BDP Type 2 WRO meetings, the response time are within 75 days and 90 days, respectively, from receipt of WRO meeting request and package.


Reasons the FDA Denies or Cancels a Meeting Request

Requests for BPD Types 2, 3, and 4 meetings are usually granted except in the most unusual circumstances. However, the FDA will deny a meeting request for any of the following reasons:

  • The meeting request is not in an appropriate format
  • The meeting request is considered by the FDA as incomplete (i.e., the request is not accompanied with a meeting package containing adequate information for FDA review)
  • Failure to pay the required BPD fees for a biosimilar or interchangeable product within the required time frame, may result in the cancellation of a scheduled meeting.

BsUFA Fees

Under the BsUFA user fee provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act), BDP fees are applied to biosimilar or interchangeable products in the BDP program. There is no fee associated with a BIA meeting. BDP fees include the initial, annual, and reactivation fees. Sponsors are encouraged to review the draft guidance of Assessing User Fees under the Biosimilar User Fee Amendments of 2017 to obtain more information related to BsUFA fees.

How to Handle Preliminary Responses from the FDA

Communications between the FDA and sponsors that take place before the formal meeting may serve as the foundation for the discussion during the meeting. However, preliminary responses from the FDA should not be considered as final responses unless there is an agreement that further discussions are not required. In addition, new information and questions should not be generated based on the preliminary responses from the FDA. Preliminary responses are sent to the sponsors or requesters no later than 5 calendar days before the face-to-face, teleconference, or videoconference meeting date for BDP Types 2 and 3 meetings. For other meeting types, preliminary responses are sent no later than 2 calendar days before the face-to-face, teleconference, or videoconference meeting.

The Formal Meeting

Formal meetings are chaired by an FDA staff. The meetings usually start with introductions and an overview of the agenda. Formal presentations during the meetings are usually not required because adequate information should have been provided in the meeting package. However, if a presentation is necessary, it should be discussed ahead of time with the FDA project manager, who will determine whether a presentation will take place during the meeting. Additionally, presentation materials should be submitted ahead of the scheduled meeting.

Meeting summaries can be generated by an FDA or a sponsor attendee. However, the FDA’s meeting minutes are the official records of meetings and have to be preserved for meeting attendees and future reference. The FDA generally issue the official meeting minutes to the sponsors or meeting requesters within 30 calendar days after the meeting.

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Feb 11

New FDA Guidances for January 2019

By Zachary Swan, Ph.D., RAC (US), Regulatory Scientist at Cato Research

 FDA draft and final guidances released from CDER, CBER, and CDRH in January are posted. In addition, upcoming advisory committee meetings are listed below with links to more information.


Special Interest Guidances/Information Date Posted
Rare Diseases: Common Issues in Drug Development Guidance for Industry Rev. 1 – Draft Guidance 31 Jan 2019
Marketing Status Notifications Under Section 506I of the Federal Food, Drug, and Cosmetic Act; Content and Format Guidance for Industry – Draft Guidance 30 Jan 2019
Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products – Final Guidance 29 Jan 2019
Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications – Final Guidance 29 Jan 2019
REMS Assessment: Planning and Reporting – Draft Guidance 24 Jan 2019
Immunogenicity Testing of Therapeutic Protein Products —Developing and Validating Assays for Anti-Drug Antibody Detection Guidance for Industry – Final Guidance 23 Jan 2019
Labeling for Human Prescription Drug and Biological Products Approved Under the Accelerated Approval Regulatory Pathway – Final Guidance 22 Jan 2019
ANDA Submissions – Amendments and Requests for Final Approval to Tentatively Approved ANDAs Guidance for Industry – Draft Guidance 16 Jan 2019
Upcoming Meetings (* = New)
February 12, 2019: Obstetrics and Gynecology Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* February 12, 2019: Obstetrics and Gynecology Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* February 26, 2019: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement
* March 6 – 7, 2019: Vaccines and Related Biological Products Advisory Committee Meeting Announcement
* March 8, 2019: Microbiology Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* March 21, 2019: Neurological Devices Panel of the Medical Devices Advisory Committee Meeting Announcement
* March 27, 2019: Meeting of the Pulmonary-Allergy Drugs Advisory Committee Meeting Announcement
Last updated: 11 February 2019


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