New FDA Guidances for January 2016

Special Interest Guidances/Information Date Posted
Design Considerations and Pre-market Submission Recommendations for Interoperable Medical Devices– Draft Guidance 26-Jan-2016
Postmarket Management of Cybersecurity in Medical Devices- Draft Guidance 22-Jan-2016
Guidance Agenda: Guidances CDER is Planning 22-Jan-2016
Implanted Blood Access Devices for Hemodialysis– Final Guidance 21-Jan-2016
Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile– Final Guidance 21-Jan-2016
Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Products– Final Guidance 14-Jan-2016
Use of Nucleic Acid Tests to Reduce the Risk of Transmission of Hepatitis B Virus from Donor of Human Cells, Tissues, and Cellular and Tissue-Based Products– Draft Guidance 8-Jan-2016
Unique Device Identification: Convenience Kits– Draft Guidance 4-Jan-2016
Upcoming Meetings (* = New)
  Meeting of the Psychopharmacologic Drugs Advisory Committee, 03 February; Silver Spring, MD
* Arthritis Advisory Committee, 03 February; Silver Spring, MD
* Cellular, Tissue, and Gene Therapies Advisory Committee, 16 February; Silver Spring, MD
  Risk Communication Advisory Committee, 16 February; Silver Spring, MD
  Risk Communication Advisory Committee, 17 February; Silver Spring, MD
  Circulatory System Devices Panel of the Medical Devices Advisory Committee, 18 February; Gaithersburg, MD
  Orthopaedic and Rehabilitation Devices Panel of the Medical Devices Advisory Committee, 19 February; Gaithersburg, MD
  Gastroenterology and UrologyDevices Panel of the Medical Devices Advisory Committee, 25-26 February; Gaithersburg, MD
  Vaccines and Related Biological Products Advisory Committee, 04 March; Silver Spring, MD
* Circulatory System Devices Panel of the Medical Devices Advisory Committee, 15-16 March; Gaithersburg, MD
* Meeting of the Psychopharmacologic Drugs Advisory Committee, 29 March; Silver Spring, MD

* new entry
Last updated: 01 Febuary 2016

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The FDA Wants To Hear Patients’ Voices

The FDA Wants To Hear Patients’ Voices

by Joanne McNelis, Ph.D., Scientist at Cato Research

In September the FDA announced the creation of its first-ever Patient Engagement Advisory Committee (PEAC) to advise the FDA commissioner on complex issues relating to medical devices, the regulation of devices, and their use by patients. This marks a major milestone in the FDA’s ongoing approach to foster a more “patient-centric” regulatory process.

The Food and Drug Administration Safety and Innovation act (FDAISA), passed by Congress in 2012, ordered the FDA to “develop and implement strategies to solicit the views of patients during product development and consider the perspectives of patients during regulatory discussions.” In response, the FDA executed several programs to obtain the views of patients during medical product development – largely through open public forums.

The first of these initiatives, announced by the Center for Drug Evaluation and Research (CDER) in 2012, was the Patient-Focused Drug Development (PFDD) program – a series of at least 20 disease-focused public meetings to obtain patient perspective on specific diseases and their treatments. In 2013 the Center for Devices and Radiological Health (CDRH) launched a complementary program, the Patient Preference Initiative (PPI). With a similar aim to the PFDD, but for devices rather than drugs, the PPI enables the patient community and other interested stakeholders to weigh in on the benefit-risk tradeoffs of medical devices.

Now, the establishment of the PEAC builds upon these previous initiatives by giving patients and patient advocates the opportunity to not only voice their opinions, but actually vote on the decision making process that impacts their lives. This is a particularly important change, as the recommendation of advisory committees historically have a great influence on the FDA’s decision to approve a new product. The PEAC will also allow FDA scientists to hear from patients early in the regulatory process, so that the FDA can make more informed decisions.

The CDRH announcement states that the committee will consist of a core of nine voting members, “who are knowledgeable in areas such as clinical research, primary care patient experience, and health care needs of patient groups in the United States.” The committee may also include ‘‘an individual nominated by industry to serve temporarily as non-voting members’’, who will be selected by The Commissioner or a designee. The PEAC will discuss a number of important patient-related topics, including “Agency guidance and policies, clinical trial or registry design, patient preference study design, benefit-risk determinations, device labeling, unmet medical needs, available alternatives, patient reported outcomes, device-related quality of life or health status issues, and other patient related topics.”

At the Regulatory Convergence Meeting in October, Stephen Ostroff, Acting Commissioner for Food and Drugs, voiced his support of the PEAC, “This advisory committee represents a new and exciting opportunity to foster patient partnerships with FDA, and it complements other efforts at FDA to bring the patient into the medical device regulatory process”. However, he also acknowledged that meaningful patient engagement was not without its challenges, “Patients have to understanding the regulatory framework, clinical trial designs and operational challenges, and the legal and practical limitations facing medical product developers”.

Time will tell if, armed with this increased patient perspective, we will see a difference in the regulatory landscape for devices, and, ultimately, if this information will trickle down to industry and affect the types of devices seeking regulatory approval.

http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM270412.pdf.

http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm347317.htm

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/PatientEngagementAdvisoryCommittee/default.htm

 https://www.federalregister.gov/articles/2015/09/21/2015-23521/establishment-of-the-patient-engagement-advisory-committee-establishment-of-a-public-docket-request

http://www.fda.gov/newsevents/speeches/ucm469673.htm

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New FDA Guidances for December 2015

By Brant Hamel, Ph.D., Regulatory Scientist at Cato Research
FDA draft and final guidances, released from CDER, CBER, and CDRH in November 2015, are posted.  In addition, upcoming advisory committee meetings to be held are also listed below with a link to more information.

 

Special Interest Guidances/Information Date Posted
Public Notification of Emerging Postmarket Medical Device Signals (Emerging Signals) – Draft Guidance 31-Dec-2015
Electroconvulsive Therapy (ECT) Devices for Class II Intended Uses– Draft Guidance 29-Dec-2015
Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base– Draft Guidance 23-Dec-2015
Safety Assessment for IND Safety Reporting– Draft Guidance 16-Dec-2015
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) – Draft Guidance 15-Dec-2015
Premarket Studies of Implantable Minimally Invasive Glaucoma Surgical (MIGS) Devices– Final Guidance 15-Dec-2015
Head Lice Infestation: Developing Drugs for Topical Treatment– Draft Guidance 14-Dec-2015
Premarket Notification Requirements Concerning Gowns Intended for Use in Health Care Settings– Final Guidance 9-Dec-2015
Best Practices for Communication Between IND Sponsors and FDA During Drug Development– Draft Guidance 4-Dec-2015
eCopy Program for Medical Device Submissions– Final Guidance 3-Dec-2015
Recommendations for Assessment of Blood Donor Suitability, Donor Deferral and Blood Product Management in Response to Ebola Virus– Draft Guidance 3-Dec-2015
Upcoming Meetings (* = New)
* Meeting of the Psychopharmacologic Drugs Advisory Committee, 12 January; Silver Spring, MD
* Vaccines and Related Biological Products Advisory Committee, 14 January; Silver Spring, MD
* Allergenic Products Advisory Committee, 21 January; Silver Spring, MD
* Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee, 22 January; Silver Spring, MD
* Meeting of the Psychopharmacologic Drugs Advisory Committee, 03 February; Silver Spring, MD
* Risk Communication Advisory Committee, 16 February; Silver Spring, MD
* Risk Communication Advisory Committee, 17 February; Silver Spring, MD
* Circulatory System Devices Panel of the Medical Devices Advisory Committee, 18 February; Gaithersburg, MD
  Orthopaedic and Rehabilitation Devices Panel of the Medical Devices Advisory Committee, 19 February; Gaithersburg, MD
* Gastroenterology and UrologyDevices Panel of the Medical Devices Advisory Committee, 25-26 February; Gaithersburg, MD
* Vaccines and Related Biological Products Advisory Committee, 04 March; Silver Spring, MD

* new entry
Last updated: 08 January 2016

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Toxicological/Safety Evaluation of Dietary Supplements Containing Vitamins and Minerals

By Harsh Sancheti, Ph.D., Medical Writer at Cato Research

Dietary supplementation of certain vitamins and minerals has resulted in significant positive public health outcomes. Some notable examples include folic acid fortification in wheat or maize flour that has reduced the risk of neural tube birth defects and fortification of milk with vitamin D that has reduced the prevalence of rickets in children. Addition of iodine to table salt, via the salt iodization programs, implemented by many countries, has resulted in a dramatic reduction in the prevalence of iodine deficiency worldwide. Although, there are some controversies around the mandatory fortification of foods, the requirement of minimum levels of vitamins and minerals for good health, is a general scientific consensus. A healthy diet is considered to be the best source of meeting these minimum levels of vitamins and minerals; however, this is not always possible due to busy life-styles, financial limitations, or the prevalence of fast food. To meet this need, several manufacturers have come up with nutritional supplements that are intended to fill gaps in nutrition and provide the daily recommended levels in a convenient, cheap, and compact form. The nutritional health supplements industry is becoming one of the fastest growing industries that is expected to reach $175 billion globally by 2020. About one in two Americans use multivitamins, and its usage has increased from 42% in 1988 to 53% in 2006. However, are these dietary supplements safe and how is their safety determined?

The safety determination of dietary supplements containing only vitamins and minerals is relatively straightforward as there are recommended or mandatory guidelines by global regulatory authorities that supplement manufacturers are expected to follow. Large clinical studies along with toxicological studies have been carried out over the years to gather data around the minimum, optimal, and maximum tolerated levels for all vitamins and minerals. These studies have been carried out in various regions of the globe resulting in most countries setting up regulatory bodies to review the data and set limits. In the U.S., the Institute of Medicine has set up dietary reference intake values and the tolerable upper limits for various vitamins and minerals. In Europe, the European Food Safety Authority has established dietary reference values and tolerable upper intake levels for vitamins and minerals. In India, the Indian Council of Medical Research has set up the recommended dietary allowances for Indians. Similarly, the Council for Responsible Nutrition was established by the major manufacturers of dietary supplements as a platform to self-regulate and have established their own recommended levels of the various vitamins and minerals based on existing scientific data. Some countries have also adopted these limits from others based on the metabolic and genetic similarities between their populations. The introduction of herbal extracts and botanical mixtures to dietary supplements containing vitamins and minerals brings in an added complexity with no straightforward answers and has been addressed in another article posted here: Toxicological/Safety Evaluation of Herbal Supplements and Botanical Combinations.

For the consumer, it is not a straightforward choice as there are hundreds of dietary supplement manufacturers to choose from. This entails that the consumer needs to educate themselves and make smart choices. Supplement manufacturers clearly spell out the amount of vitamins and minerals in each tablet and how much that corresponds in terms of the daily requirement. This is usually expressed as percentage of daily value supplied by one serving of the supplement. Consumers with the help of their medical doctor and an assessment of their typical eating habits can make the choice of selecting one supplement over the other. Importantly, a particular vitamin is generally an umbrella term for the different chemically available forms (e.g., ascorbic acid is the most common form of vitamin C, but not the only form of vitamin C). Although there are some claims around one form of vitamin being better than the other, most major manufacturers use industry standard chemically synthesized forms of vitamins and minerals. On the other hand, some manufacturers rely on natural sources of vitamins and minerals. The difference between the two in terms of its chemical action is a debatable issue and out of the scope of this article.

The two main reasons for safety concerns of supplements containing only vitamins and minerals could be 1) ingesting multiple supplements containing the same vitamins and minerals leading to an additive high intake of individual vitamins and minerals; possibly resulting in minor or reversible adverse effects and in rare cases could lead to serious adverse effects 2) impure supplements supplied by manufacturer resulting in serious adverse effects due to ingestion of unknown harmful ingredients. The former can be simply avoided by educating oneself about the contents of a supplement and taking the advice of a medical doctor in combining multiple supplements while the latter is a more complicated problem that can perhaps be avoided by buying supplements from a reputed brand. An important point to understand here is that most dietary supplements are required to supply at-least the minimum amounts of vitamins and minerals claimed on their label until the expiration date of that supplement. This means that dietary supplements are required to contain the minimum amounts of the individual vitamins and minerals (as claimed on the label) from the date of manufacture until the date of expiration (could be 1-2 years). Since vitamins can degrade over a period of time, manufacturers have to add significantly more vitamins than claimed on the label at the time of supplement manufacture (to account for its degradation until expiration date); these additional amounts added during manufacturing could be as high as 50% in some cases. Thus, it is not recommended for consumers to mix several supplements containing the same vitamins and minerals as this could result in crossing the maximum tolerable levels of those vitamins and minerals (you may be ingesting far more vitamins and minerals from a recently manufactured supplement as opposed to one close to its expiration date).

Major supplement manufacturers will have Toxicologists to assess the safety of a dietary supplement product. These include the safety evaluations of individual ingredients and the combined formula. A consumer should always take the opinion of a medical doctor before starting any dietary supplementation since individual genetics and metabolism vary widely. In some cases, ingestion of high amounts of a particular vitamin or mineral may not be suited (e.g., high folic acid intake may mask vitamin B12 deficiency until its neurological consequences become irreversible). Moreover, a consumer should stay well-informed by educating themselves about the ingredients in a supplement, explore the manufacturer websites for additional information, or even reach out directly to the manufacturer for any safety concerns or questions. Consumers must also be warned of several un-scientific websites making ostentatious claims about supplements. Legitimate information about several dietary supplements can be found on reliable websites like the NIH Office of Dietary Supplements, Health Canada, European Food Safety Authority, and the Council for Responsible Nutrition. As a general rule, with vitamins and minerals supplementation, as is true with most other things in life, too much or too little is typically harmful.

 

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Toxicological/Safety Evaluation of Herbal Supplements and Botanical Combinations

Toxicological/Safety Evaluation of Herbal Supplements and Botanical Combinations

by Harsh Sancheti, Ph.D., Medical Writer at Cato Research

Plants all around us show an astonishing ability to grow in some of the most taxing conditions, fight deadly viruses (without even a leaf moving – quite figuratively), provide nutrition and food sources, and have been historically used all around the world for herbal remedies. However, since the days of stone-age are far behind us, humans no longer go on forest excursions, wandering for herbal remedies. In our modern times, the equivalent of a stone-age excursion would be a trip to the grocery store or better, get online and shop. To meet this need, several manufacturers have come up with herbal extracts and botanical combinations that are ascribed to have potential therapeutic value. The wide-spread availability of herbal supplements all around us (in grocery stores and online) is a testament to its popularity. Recent years have seen increasing consumer awareness about the potential benefits of dietary supplements (including herbal supplements) and this has resulted in the nutritional health supplement industry becoming one of the fastest growing industries that is expected to reach $175 billion globally by 2020. About one in five American adults use herbal supplements. However, are herbal supplements safe? Safety issues with certain herbal supplements like Ephedrine Alkaloids and Kava are well documented with the FDA advising consumers against using such supplements. Two recent incidences re-kindle this long-standing question, the collapse of Lamar Odom after speculated ingestion of herbal Viagra and a review in New England Journal of Medicine showing that, dietary supplements results in an estimated 23,000 visits to the emergency room.

The safety of herbals supplements needs to be thoroughly evaluated since the risk-benefit ratio would not justify an herbal supplement with major adverse effects. Historical use of supplements has shown several individuals with major side effects after using impure or incorrectly characterized supplements. Moreover, the regulations around the globe for marketing herbal supplements vary widely. Markets like the United States almost require no animal safety testing (pre-clinical) or clinical studies. On the other hand, markets like Korea require substantial supporting safety documents including pre-clinical and clinical studies. It is also important to note that most herbal supplements are made of multiple herbal extracts (i.e., an herbal supplement typically has extracts from different plants and various parts of the plants). So how do you prove the safety of herbal supplements or establish a safe dose? In some cases, a careful and thorough evaluation of the existing scientific literature is enough, whereas, in other cases, additional pre-clinical and clinical studies are required. The major steps that could be taken in determining the safety of herbal supplements are outlined below:

  • Characterization – The first step should be the chemical characterization of different herbal extracts contained in the supplement. This includes identifying the major chemical constituents (terpenoids, flavonoids, etc.). There should be a thorough evaluation and understanding of which parts of the plants are being used to make the extracts (leaf, seeds, stem, etc.) and the differences in the chemical constituents among these parts. Different parts of the plants can have significantly different chemical constituents. Some Quantitative Structure Activity Relationship information can be used for safety evaluation; however, this is typically quite complex with herbal extracts since there are several active chemicals. It is also important to understand how the herbal extracts are prepared. Herbal extracts are typically prepared by concentrating the specific part of the plant (e.g., leaf, root) in a specific solvent (e.g., water, ethanol, methanol, hexane), followed by concentration techniques (e.g., evaporation, superfluid extraction), and finally drying it into a powder or other forms. The resulting herbal extract may contain several-fold of the active plant chemicals (2 – 100 fold or more). Basically, it would mean that several grams of the specific plant part used is concentrated into one small tablet containing all of the active chemicals in it. A cognizance of the chemical ingredients, their potency, and how chemicals from different plants interact is critical in safety evaluation. Thus, the full characterization of an herbal supplement includes identifying all of the active chemical constituents and understanding the final amount of chemical constituents being delivered via the herbal extract.
  • Toxicological and Human Safety Data – A thorough literature review about the existing Toxicological and Human safety data for the different plant extracts being used should be carried out. This entails sifting through several public databases like PubMed, TOXNET, IRIS, TOXLINE, and carrying out plant specific toxicological study searches and extracting clinical data about human use. A thorough explanation about the databases, search methods, search strategies, and data extraction is out of the scope of this article, however, the primary end result from these searches is getting information about the levels of specific plant extracts that have been used safely and understanding their toxicological profile. More importantly, getting information about the no-observed-adverse-effect-levels (NOAEL) (an amount at which no adverse effects are seen) is crucial. If there is inadequate information in existing scientific literature about the plant extracts or a clear understanding of the possible effects of mixing multiple extracts is lacking, additional studies have to be carried out. These include animal toxicological testing such as toxicokinetics, acute, sub-chronic, and chronic toxicity testing along with other tests such as phototoxicity, genotoxicity, or carcinogenicity where applicable. The clinical safety testing includes an assessment of adverse effects, blood and liver tests along with specific tests as applicable for a product.
  • Safety Report – Using all the information collected in the first two steps along with the history of use for a particular plant extract, a Toxicologist would prepare a safety report that captures its chemical composition, history of use, pre-clinical toxicological data, clinical data about safety, and possible contraindications due to use of another herb or drug. All of this information is then used by the Toxicologist to determine the safe dosage for humans as the acceptable daily intake (ADI). This is primarily based on the NOAEL value and taking into consideration several folds of safety margins (typically, 100-fold). Generally, much lower doses of herbal extracts are recommended to humans than those found to be safe in animals; this accounts for the differences in species and sensitivity among humans.

Minor modifications to a safe herbal supplement, such as changes in parts of the plant used, extraction solvents, extraction methods, extract combinations, extraction ratios, and potency can result in major changes in the toxicological profile of an herbal supplement and affect its safety. A responsible herbal supplement manufacturer would have the safety program for supplement safety imbued in the product conception and product development phase rather than carrying out a safety evaluation after the final product has been produced. Although, a thorough safety evaluation should be carried out by every supplement manufacturer, several supplement manufacturers do not have the resources to carry out such studies and get a scientific understanding. This results in a cocktail mixture of herbal supplements with no scientific safety understanding.

For a consumer considering taking a herbal supplement, educating themselves about the herbal supplements along with taking the opinion of a medical doctor are extremely important and can prevent health complications. Several consumers assume that herbal supplements have no adverse effects; on the contrary, they could have major adverse effects. It is important to understand that most pharmacological drugs have only one active chemical, whereas, herbal supplements are a mixture of several chemicals of which, some are quite potent. Moreover, a pharmacovigilance program tracking adverse effects due to health supplements is rarely carried out. Importantly, the regulatory environment for herbal supplements is changing globally and several countries are in process of regulating herbal products more stringently. This is expected to prevent quackery and control the ostentatious claims. Generally, if the claims are too good to be true, they are too good to be true!

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