New FDA Guidances for October and November 2016

By Michelle Villasmil, Ph.D., Regulatory Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH in October and November 2016 are posted. In addition, upcoming advisory committee meetings to be held in the next month are listed below with links to more information.


Special Interest Guidances/Information Date Posted
Mitigating the Risk of Cross-Contamination from Valves and Accessories Used for Irrigation Through Flexible Gastrointestinal Endoscopes – Final Guidance 29 Nov 2016
Providing Postmarket Periodic Safety Reports in the ICH E2C(R2) Format (Periodic Benefit-Risk Evaluation Report) – Final Guidance 28 Nov 2016
Submission of Quality Metrics Data Guidance for Industry – Draft Guidance 23 Nov 2016
Nonprescription Sunscreen Drug Products – Format and Content of Data Submissions – Final Guidance 22 Nov 2016
Contract Manufacturing Arrangements for Drugs: Quality Agreements – Final Guidance 22 Nov 2016
Nonprescription Sunscreen Drug Products – Safety and Effectiveness Data – Final Guidance 22 Nov 2016
Safety Testing of Drug Metabolites – Final Guidance 22 Nov 2016
Generic Drug User Fee Amendments of 2012: Questions and Answers Related to User Fee Assessments – Final Guidance 21 Nov 2016
Submission of Premarket Notifications for Magnetic Resonance Diagnostic Devices – Final Guidance 18 Nov 2016
BCG-Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment – Draft Guidance 17 Nov 2016
Product Labeling for Certain Ultrasonic Surgical Aspirator Devices – Draft Guidance 10 Nov 2016
Medical Device Reporting for Manufacturers – Final Guidance 08 Nov 2016
Clinical Considerations for Investigational Device Exemptions (IDEs) for Neurological Devices Targeting Disease Progression and Clinical Outcomes – Final Guidance 07 Nov 2016
Non-Inferiority Clinical Trials – Final Guidance 07 Nov 2016
Revised Recommendations for Determining Eligibility of Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products Who Have Received Human-Derived Clotting Factor Concentrates – Final Guidance 01 Nov 2016
Labeling for Permanent Hysteroscopically-Placed Tubal Implants Intended for Sterilization – Guidance for Industry and Food and Drug Administration Staff – Final Guidance 31 Oct 2016
Collection of Race and Ethnicity Data in Clinical Trials – Guidance for Industry and FDA Staff – Final Guidance 26 Oct 2016
Low Sexual Interest, Desire, and/or Arousal in Women: Developing Drugs for Treatment Guidance for Industry – Draft Guidance 25 Oct 2016
Software as a Medical Device (SaMD): Clinical Evaluation – Draft Guidance 14 Oct 2016
ANDA Submissions – Prior Approval Supplements Under GDUFA – Final Guidance 14 Oct 2016
Blood Glucose Monitoring Test Systems for Prescription Point-of-Care Use – Guidance for Industry and Food and Drug Administration Staff – Final Guidance 11 Oct 2016
Self-Monitoring Blood Glucose Test Systems for Over-the-Counter Use – Guidance for Industry and Food and Drug Administration Staff – Final Guidance 11 Oct 2016
Sunscreen Innovation Act: Withdrawal of a 586A Request or Pending Request Guidance for Industry – Final Guidance 07 Oct 2016
Sunscreen Innovation Act: Section 586C(c) Advisory Committee Process – Final Guidance 07 Oct 2016
Head Lice Infestation: Developing Drugs for Topical Treatment Guidance for Industry – Final Guidance 05 Oct 2016
Tropical Disease Priority Review Vouchers – Final Guidance 05 Oct 2016
Acetaminophen; Oxycodone hydrochloride_204031 – Draft Guidance 04 Oct 2016
Upcoming Meetings (* = New)
* Bone, Reproductive and Urologic Drugs Advisory Committee; 06 December 2016; Silver Spring, MD
* 2017 Advisory Committee Tentative Meetings
* new entry

Last updated: 30 November 2016



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NORD Summit 2016 Highlights

By Kimberley Cummings, Ph.D., RAC (US), Vice President, Scientific & Regulatory Strategy and Operations Cato Research


The National Organization for Rare Disorders (NORD) held their annual Rare Diseases and Orphan Products Breakthrough Summit in Arlington, VA on October 17th and 18th.  If you have never been to this meeting before, it is the most unique and interesting mix of FDA representatives (and we are talking BIG names, too!), pharmaceutical/industry representatives, policy analysts, and patient advocacy groups along with several patients themselves.  That combination of individuals will certainly lead to some thought-provoking discussions, and if you follow any other industry blogs, then you have likely already seen some interesting highlights from this conference.

At last year’s Summit, the biggest news regarding Patient-Focused Drug Development and patient advocacy was that patients were, in fact, helping forge a path to approval as evidenced by the development and subsequent release of the FDA’s Guidance for Industry: Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment, a guidance largely drafted by the Duchenne advocacy community.  So, it was no surprise that this year, the discussion continued around potential drugs for Duchenne’s Muscular Dystrophy, but mostly on the recent somewhat controversial approval of Sarepta’s Exondys 51 (eteplirsen).  Not once or even twice, but at least three during the various sessions I attended, did an FDA or industry representative express their opinions on the approval of Exondys 51 only to result in an emotional rebuttal comment from a parent and/or advocate.  Clearly, charged conversations occurred during the approval process, and are still lingering today.

Rest assured, there were many other informative discussions that took place over the course of the 2-day summit.  Session topics included genetic innovation, advancing diagnoses, challenges of access and reimbursement, progress through policy, and understanding the pipeline and investment landscape for rare diseases and orphan products.  Presented here are some of the important take‑away messages from these various discussions:

  1. Rigorous data exploration has been and must remain the driver for drug development. Orphan drugs tend to be innovative (ie, first in class) and take advantage of FDA’s special programs, but development and approval must be based on strong science.  Furthermore, the development programs need to keep up with the ever-evolving science including innovations in telemedicine, genetic phenotyping, biosimilars, and advancements in CRISPR (clustered regularly interspaced palindromic repeat) technology, just to name a few.  In response to some of these advancing technologies, FDA has even reorganized to provide better oversight of gene therapy products; the office formerly known as the Office of Cellular, Tissue and Gene Therapies (OCTGT) has now become the Office of Tissues and Advanced Therapies (OTAT).  The formation of OTAT involves the transfer of the Office of Blood Research and Review’s Division of Hematology Clinical Review and Division of Hematology Research and Review, along with appropriate support staff, to OCTGT to constitute the new office.  The products now regulated by OTAT include all purified and recombinant versions of therapeutic proteins for hematology.


  1. Collaboration must continue between patient advocacy groups and the FDA, as well as among researchers through consortia. No one can hold all the knowledge.  This thinking is also supported by the Final Rule for the registering of studies and posting of results on  A panel discussion on collaboration across borders identified the increased interactions between FDA and EMA in regards to rare disease programs and suggested more international patient advocacy groups.  Furthermore, this panel confirmed the need for patient-driven registries, by disease, not by company, to collect natural history data and suggested a global depository system with standardized terms.  Progress in global outreach was substantiated by the establishment of the United Nations Committee for Rare Diseases.  This Committee will serve as an advocacy platform uniting around the issue of rare diseases a diversity of constituents which need to be more closely connected and collaborating with each other, including: the international non-governmental (NGO) community, major UN agencies, national governments, the academic and scientific world as well as the private sector.  The formal inauguration of the Committee is currently scheduled for November 11, 2016 at the United Nations headquarters in New York.


  1. In regards to patient advocacy collaboration, FDA continues to conduct the Patient Focused Drug Development (PFDD) meetings per the PDUFA V goals. A total of 24 PFDD meetings were planed from FY 2013-2017, and include the publication of a “Voice of the Patient” upon completion of the meeting.  To date, 20 meetings have been conducted, and only 4 remain.  These final 4 meetings will examine sarcopenia, autism, alopecia areata, and hereditary angioedema.  Upon completion of this PDUFA V goal, externally led PFDD meetings are expected to continue.  Meetings will be attended, but not organized by FDA; rather, a patient advocacy group or consortia would submit a letter of intent to the FDA 1 year in advance of the anticipated meeting date outlining the time, location, goal, objectives, outreach effort, and expected collaboration for the meeting.  Meeting organizers would also be expected to produce a “Voice of the Patient” report on their own website.


  1. FDA speakers confirmed for their audience that randomized clinical trials are the fastest way to determine clinical effectiveness. Especially in rare disease populations, every subject is critical, so valuable resources – either the subject themselves or a subject’s samples, should not be misused or wasted on poorly designed clinical trials.  To that end, the paradigm of early open-label studies shifted to randomizing subjects with rare diseases as early as possible and minimize time on placebo.  Emphasis was placed on the use of validated biomarkers and the need to report trial results early and accurately to obtain input from the FDA in regards to the clinical relevance of the biomarker and the plan for accelerated approval.  The audience was reminded that accelerated approval is NOT a rescue for a failed program, and that “any” effect of a drug on a biomarker does not equate to accelerated approval. Only a clearly defined and clinically relevant effect would suffice for accelerated approval.  Finally, post-hoc analyses should be used to design the next clinical trial, not as a basis for approval.


  1. As Natural History studies remain a critical component of rare disease and orphan product development, all stakeholders need to understand the natural history of a disease, and prospectively identify any natural history external controls. In regards to understanding the natural history of a disease, the Office of Orphan Product Development launched the Orphan Products Natural History Grants Program in 2016.  The goal of the grants program is to support studies that advance rare disease medical product development through characterization of the natural history of rare diseases/conditions, identification of genotypic and phenotypic subpopulations, and development and/or validation of clinical outcome measures, biomarkers and/or companion diagnostics.


  1. Officials at FDA working with rare diseases and orphan indications remain committed and VERY busy. Over the past 6 years, OOPD has seen a doubling of the number of orphan designations requests and will likely see a record number of designation requests this year.  To keep up with this demand, OOPD has had to expand the review time of a designation request from 90 days to 120 days.


Paul Melmeyer, NORD’s Associate Director of Public Policy, said it best when he said, “If you have a drug in the FDA process in the next 6 years, you should be involved with PDUVA VI.”  Given the timing of this meeting so close to a Presidential election, there was a particularly strong policy component to this year’s summit.  With the upcoming authorization of PDUFA VI, proposed bills already in review in Congress (including 21st Century Cures), and potential major healthcare changes with the approaching election, the next few months and years to come should bring about some small, and some not so small, changes in drug development, particularly for rare diseases and orphan indications.


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Precision Medicine and the FDA

by Reshma Jagasia, Ph.D., Scientist at Cato Research

“Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals. You can match a blood transfusion to a blood type — that was an important discovery. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature?” — President Barack Obama, January 30, 2015


While this concept seems to touch on science fiction, the FDA is nevertheless gearing up to embrace this new approach to healthcare in their regulatory oversight. Let us start with some definitions.


What is Precision Medicine?

The current format of healthcare is to provide standardized treatments to individual patients. It is a one-size-fits-all approach to medicine that often works. However, in many cases, treatment is non-optimal or fails altogether because little or no adjustment could be made for a patient’s unique situation.

Precision medicine is an innovative approach to healthcare in which medical decisions, practices, and products are tailored to the individual patient, their genetics, environment, and lifestyle. Customization can be applied in diagnosis and intervention, drug development and usage, and cancer genomics, and almost certainly begins with diagnostic testing or other molecular or cellular analyses. Already several FDA-approved treatments have been tailored to a patient’s genetic makeup or the genetic profile of a patient’s tumor. In fact, cancer patients routinely undergo genetic testing as part of patient care, potentially enabling physicians to improve chances of survival and to reduce exposure to adverse events.

President Obama signed the Precision Medicine Initiative (PMI) in January, 2015, infusing $215 million into the advancement of this medical movement.


What is Next-Generation Sequencing?

Many advances in precision medicine will depend on the use of next generation DNA sequencing (NGS), a catch-all term used to describe a number of modern, high-throughput sequencing technologies that are much faster and less expensive compared with traditional techniques. NGS enables broad and deep sequencing of a portion of a gene, an entire exome, or a whole genome, with clinical application for diagnosis, risk prediction, and treatment for a disease or condition. The rapid adoption of NGS-based tests in both research and clinical practice is leading to the increased identification of genetic variants, including rare variants that may be unique to a single individual or family lineage. Understanding the clinical significance of these genetic variants is key to the future of precision medicine.


How Has the FDA Responded?

To help accelerate research and the clinical adoption of the PMI, the FDA is focused on optimizing their regulatory oversight for NGS in vitro diagnostics (IVDs) to help assure the safety and effectiveness of these tests. While most IVDs typically detect a limited number of analytes to diagnose pre-specified conditions, NGS-based tests can measure millions of analytes (i.e., bases) associated with numerous conditions. Moreover, the intended uses of NGS-based tests are often broad, and the nature of the resulting clinical information and types of genetic variants is often unknown until after the test has been conducted. As a result, shaping the appropriate regulatory oversight for NGS-based tests presents a challenge for the FDA.

Recently, the FDA has released two draft guidance documents outlining the proposed regulatory oversight for NGS-based tests intended to aid in the diagnosis of individuals with suspected germline diseases. The FDA has crafted its regulatory approach to be appropriately flexible and adaptive to accommodate innovation and evolution in development and validation while still assuring that NGS-based tests provide accurate and useful results.


The New Draft Guidances

Use of Standards in FDA’s Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases

This guidance document, when finalized, will provide recommendations for designing, developing, and validating NGS-based tests intended to aid in the diagnosis of individuals with suspected germline diseases or other conditions. The recommendations apply to these tests whether results are provided directly to patients or through healthcare professionals; however, for the former, additional recommendations and controls would be required. This draft guidance document does not apply to NGS-based tests intended for stand-alone diagnostic purposes, screening, microbial genome testing, risk prediction, cell-free DNA testing, fetal testing, pre-implantation embryo testing, tumor genome sequencing, RNA sequencing, or use as companion diagnostics, as these uses may require further analytical characterization.

To date, the FDA has cleared a small number of single-gene, disease-specific, targeted, NGS-based tests, but has not previously classified NGS-based tests with a broad intended use for suspected germline diseases. As a result, such tests are automatically classified into class III by operation of law. There are currently no legally marketed devices of this type that could serve as a predicate device in a premarket notification under section 510(k) of the Federal Food, Drug and Cosmetic Act (FD&C Act). Thus, these NGS-based tests are subject to FDA approval of a premarket approval application (PMA).

The draft guidance document outlines considerations for possibly classifying certain NGS-based tests for germline diseases in class II, potentially exempting them from premarket notification requirements. Specifically, The FDA encourages that applicants submit a de novo request for classification by operation of section 513(f)(1) of the FD&C Act. This request is applicable when there is not a legally marketed predicate device on which to base substantial equivalence in a 510(k), and the applicant believes that the test is appropriate for classification in class I or class II. If the de novo request for class II classification is granted, the test may then be marketed, serve as a predicate for future 510(k) submissions, and would be subject to both general and special controls.

Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics

There are numerous publicly accessible databases of human genetic variants that can serve as sources of valid scientific evidence to support the clinical validity of genotype-phenotype relationships. This draft guidance document describes recommendations that would confer recognition to these databases as sources of valid scientific evidence supporting the clinical validity of NGS tests. Criteria under consideration includes:

  • types of variants in the database (e.g., germline, somatic);
  • the use of standard operating procedures (SOPs) for general operation, confidentiality and privacy of patient health information, data security, curation, variant interpretation, and reinterpretation;
  • personnel qualifications;
  • the plan for data preservation; and
  • policies for conflict of interest and their disclosure.

This draft guidance document also outlines the process by which database administrators could apply to the FDA for recognition, and how the FDA would review such applications and periodically reevaluate the recognized databases.

The FDA’s engagement in the PMI is foundational, establishing regulatory controls that encourage advancement in genomic testing while assuring that NGS-based tests are safe and effective. These two new guidances, once finalized, will strike that important balance between safeguarding public health and promoting innovation.

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New FDA Guidances for September 2016

By Sheila R. Plant, Ph.D., R.A.C., Regulatory Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH in September 2016, are posted. In addition, upcoming advisory committee meetings to be held in the next month are listed below with links to more information.


Special Interest Guidances/Information Date Posted
Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients – Draft Guidance 30 Sep 2016
Self-Identification of Generic Drug Facilities, Sites, and Organizations – Final Guidance 22 Sep 2016
Reporting of Computational Modeling Studies in Medical Device Submissions – Guidance for Industry and Food and Drug Administration Staff – Final Guidance 21 Sep 2016
Coordinated Development of Antimicrobial Drugs and Antimicrobial Susceptibility Test Devices – Draft Guidance for Industry and Food and Drug Administration Staff 21 Sep 2016
FDA’s Application of Statutory Factors in Determining When a REMS Is Necessary – Draft Guidance 20 Sep 2016
S9 Nonclinical Evaluation for Anticancer Pharmaceuticals–Questions and Answers – Draft Guidance 16 Sep 2016
Recommendations for Microbial Vectors Used for Gene Therapy – Final Guidance 15 Sep 2016
Qualification of Biomarker Total Kidney Volume in Studies for Treatment of Autosomal Dominant Polycystic Kidney Disease Draft Guidance for Industry – Final Guidance 15 Sep 2016
Qualification of Biomarker Plasma Fibrinogen in Studies Examining Exacerbations and/or All-Cause Mortality in Patients With Chronic Obstructive Pulmonary Disease Guidance for Industry – Final Guidance 14 Sep 2016
Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Living Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) – Final Guidance 12 Sep 2016
510(k) Third Party Review Program – Draft Guidance for Industry, Food and Drug Administration Staff, and Third Party Review Organizations – Draft Guidance 12 Sep 2016
S3A Guidance: Note for Guidance on Toxicokinetics: The Assessment of Systemic – Draft Guidance 8 Sep 2016
E17 General Principles for Planning and Design of Multi-Regional Clinical Trials – Draft Guidance     8 Sep 2016
Guidance for the Submission of 510(k)s for Solid State X-ray Imaging Devices – Final Guidance (supersedes guidance dated 06 Aug 1999) 1 Sep 2016
Upcoming Meetings (* = New)
* Meeting of the Antimicrobial Drugs Advisory Committee; 4 November 2016; Silver Spring, MD


Meeting of the Pharmacy Compounding Advisory Committee Advisory Committee Meeting; 3 November 2016; Silver Spring, MD
* November 1-2, 2016: National Center for Toxicological Research Science Advisory Board Meeting; 1-2 November 2016; Little Rock, AR


Allergenic Products Advisory Committee Meeting; 27 October 2016; Silver Spring, MD


Technical Electronic Product Radiation Safety Standards Committee Meeting; 25-26 October 2016; Gaithersburg, MD
Vaccines and Related Biological Products Advisory Committee Meeting; 13 October 2016, Silver Spring, MD
Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee – 19 October, Silver Spring, MD
Allergenic Products Advisory Committee Meeting; 27 October 2016, Silver Spring, MD
* new entry

Last updated: 12 October 2016

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The Current Implementation of the Drug Supply Chain Security Act (DSCSA) Implementation Plan and Rare Disease Drugs

What is the Drug Supply Chain Security Act (DSCSA)?

In November 2013 the Drug Quality and Security Act (DQSA) was signed into law with the intent to decrease incidence of counterfeit, falsified, or substandard prescription medication.  Title II of this act was the Drug Supply Chain Security Act (DSCSA), which lays the ten-year framework for the implementation of an interoperable system capable of identifying and tracing prescription drugs as they are distributed throughout the United States.  Starting in November 2017 manufacturers will be required to include new identifiers on all drugs products at the package level (serialization); specifically, a national drug code, serial number, and barcode.  Using these identifiers, all drug transactions must be entered into an interoperable record (electronic or paper) which contains the transaction information, transaction history, and transaction statements.  These records will be maintained by the current or new product tracing systems which must meet DSCSA requirements.   Meeting these requirements will require close cooperation between drug manufacturers, dispensers, distributors, logistics, and the FDA itself.

What is Covered by the DSCSA?

The DSCSA covers prescription drugs in their finished dosage form (such as capsules, tablets, lyophilized products before reconstitution, etc.) for administration to a patient.  The Act exempts blood or blood components intended for transfusion, radioactive drugs or radioactive biological, imaging drugs, any medical gas, homeopathic drugs, and drug requiring compounding [DSCSA Section 582. Definitions (13)].

Exemption Waivers

In addition to the exemptions outlines above, the DSCSA outlines the need for the FDA to establish a process by which a waiver from any DSCSA requirement may be obtained [DSCSA Section 582. Requirements (3)(A)(i-iii)].  The process was supposed to go into effect within two years of its enactment (2013), however as of 15 September 2016 the FDA has yet to issue guidance on this topic.  Consideration of exemption waivers, however, is currently scheduled on the regulatory agenda for 2016.  It is therefore unclear under what circumstances waivers are likely to be granted, though the law does specifically mention undue economic hardship or emergency medical reasons, including a public health emergency, as grounds for such a request.

The DSCSA and Rare Disease Drugs

The costs of implementing serialization may hit orphan drugs disproportionately hard as initial costs to serialize a drug are high, and drugs targeting larger markets are likely to benefit from economy of scale.  This is particularly true of drugs targeting small patient populations that are only manufactured sporadically.  One recent survey of pharmaceutical packaging companies carried out at Cato Research Ltd. found small scale serialization costs alone can range up to $185,000 per batch of labeled drug, potentially creating a significant impact on the cost of drugs produced at small scales.  Such drugs seem likely to be good candidates for a DSCSA waiver, though this remains unclear until the FDA issues guidance.

More information about the DSCSA can be found at the FDA:


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