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February 21, 2014

Prescription Drug TV Advertisements--How Do You Know Which Are Actually the Serious Drug Risks?

TVad.pngYou can hardly watch television without seeing a prescription drug advertisement. Often the most memorable part of the advertisement is the required voiceover disclosing a long list of all the risks associated with taking the drug. The problem becomes deciphering which risks are actually the serious ones. FDA seeks to find out if that long disclosure of risks results in "reduced consumer comprehension, minimization of important risk information, and potentially, therapeutic noncompliance due to fear of side effects."

On February 18, 2014, FDA issued a notice seeking comments about its proposed collection of information - "Disclosure Regarding Additional Risks in Direct-to-Consumer (DTC) Prescription Drug Television (TV) Advertisements (Ads)." FDA proposes to investigate the impact of limiting the risk disclosure in prescription drug television advertisements to only those that are "serious and actionable" plus an alert that there are other risks associated with the drug but which are not disclosed in the advertisement.

FDA would like to hear from you by April 21, 2014 about: whether you think its investigation is necessary "for the proper performance of FDA's functions;" whether the information will have practical utility; the validity of the methodology and assumptions its investigation will use; how the quality, utility and clarity of the information collected can be enhanced; and how the collection of information can be less burdensome on respondents.

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January 31, 2014

Liquid Dietary Supplements and Beverages: How Do You Distinguish?

liquids.jpgWhether a beverage or a dietary supplement, liquid products are marketed more than ever before--now containing a wider array of ingredients, for many more intended uses and including traditional food substances, but at levels far exceeding previously used amounts. So how does one know if a liquid product is a beverage or a dietary supplement? And what regulations must be followed? To answer those questions, FDA has issued nonbinding recommendations in two new guidances this month: Distinguishing Liquid Dietary Supplements from Beverages and Considerations Regarding Substances Added to Foods, Including Beverages and Dietary Supplements. FDA hopes that these guidances will help the industry avoid misbranding with inconsistent product category labeling and adulteration for failure to meet the proper regulations.

When distinguishing between beverages and dietary supplements, as a general rule, dietary supplements are meant to supplement the diet, and beverages are for quenching thirst and providing fluid, nutritive value, taste or aroma. FDA's Guidance sets out the following factors to consider in distinguishing between the two types of liquid products: labeling and advertising, product name, product packaging, serving size and recommended daily intake, recommendations and directions for use, marketing practices, and composition of the liquid product. The Guidance provides examples of how the factors can come into play in a determination. It is likely that a combination of factors, not one, will be determinative of a product's category. For example, even if the label of a liquid product contains a Supplement Facts Panel, it could still be considered a "beverage" if it also contains a statement that the product "refreshes," or the product could be a "food" if the label contains a picture of the liquid being poured onto a salad. The product name could also be determinative that a product is likely a "beverage", if the product name contains conventional terms for beverages, like "drink", "soda", "orange juice", "iced tea", "bottled water", or "coffee". The product packaging is another determinant and, if the packaging is reclosable, is shaped similar to a common beverage package, or contains a single serving, then it is likely a "beverage". The serving size or recommended daily intake may also indicate which category a liquid product falls under. For example, if the product is intended to be consumed all at once or contains a significant part of the entire daily drinking fluid intake for the average person then it is likely a "beverage". Interestingly, marketing practices, another factor, such as metatags for "sodas," "juices" or "beverages," or paying for store shelf placement with other beverages could be determinative of a "beverage". But the product is not necessarily a "beverage" if the marketing says the product should be taken with a meal, since dietary supplements are often recommended for use along with a meal. Finally, the composition of a liquid product may be determinative, although there is a lot of overlap now with both categories containing amino acids, proteins, and vitamins. Similarly, merely adding a dietary ingredient does not make a product a "dietary supplement".

Once the factors are considered to determine whether a liquid product is a "beverage" or a "dietary supplement", the type of product controls which regulations must be met. For beverages, a substance can be generally recognized as safe ("GRAS") for its intended use based upon generally-available evidence of safety recognized by experts. But unless GRAS for its intended use or exempt, substances intentionally added to "beverages" are "food additives", which require premarket approval based upon safety data. FDA issues regulations for approved food additives that specify the conditions for which the substance is safe and can be used. Accordingly, non-dietary ingredients added to supplements, such as binders, excipients and fillers, however, must meet food additive requirements or be GRAS. On the other hand, dietary ingredients included in dietary supplements are not required to be GRAS and are exempt from food additive regulations but still must not be adulterated, and, if new, must meet new dietary ingredient requirements. No matter a "beverage" or "dietary supplement", the guidances remind the industry to make sure the labeling is not false or misleading, and if included, to make sure health claims, nutrient content claims, and structure function claims are proper.

January 17, 2014

Interactive Promotional Media Guidance (Social Media Plus) Issued in Draft by FDA

socialmedia.jpgEarlier this week, FDA released a new draft guidance, "Fulfilling Regulatory Requirements for Postmarketing Submissions of Interactive Promotional Media for Prescription Human and Animal Drugs and Biologics". This Guidance is a long-anticipated guidance regarding how FDA views what it calls "interactive promotional media" including what is commonly referred to as "social media", e.g., Facebook, Twitter, blogs, as well as networking sites, live podcasts, and online communities. In particular, FDA describes how applicants/sponsors ("firm") are expected to comply with providing the firm's promotional activities in this arena.

First, FDA explained that a firm is accountable for all promotional activities that are carried out by the firm or on the firm's behalf, including communications about the firm's product(s) that may be influenced or controlled in whole or in part by the firm. In this regard, FDA provided specific examples to illustrate the following principles:

  1. A firm is responsible for product promotional communications on sites that are owned, controlled, created, influenced, or operated by, or on behalf of, the firm.

  2. Under certain circumstances, a firm is responsible for promotion on third-party sites.

  3. A firm is responsible for the content generated by an employee or agent who is acting on behalf of the firm to promote the firm's product.

Some of the nuances described in the examples clarify that a firm's mere financial promotion of a site is not sufficient to trigger inclusion of the site as part of the firm's promotional activities. If a firm merely provides information to be included in the site, then the firm is responsible to provide that content to FDA as promotional activities. Whenever the firm has some influence or control over the content or placement of content, then the firm needs to provide the full site or partial site. If only influencing placement, the actual information and surrounding pages may be provided to put the placement in context. FDA, however, will not review user-generated content ("UGC"), e.g., message boards and chat rooms, that is "truly independent of the firm (i.e., is not produced by, or on behalf of, or prompted by the firm in any particular)."

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January 2, 2014

Cellular and Gene Therapy Advisory Committee Meeting Rescheduled for February 2014

genetherapy.jpgOn February 25-26, 2014, FDA will hold a meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee. A majority of the meeting will concern oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease or treatment of infertility. While FDA will post meeting materials at least two business days before the meeting, one item that will likely be discussed is a workshop held in September 2002 on Evidence Based Assisted Reproductive Technologies (ART) that concerned oocyte modification. Approximately half of the second day will focus on considerations for the design of early-phase clinical trials of cellular and gene therapy products, which was the topic of a revised guidance published on July 2, 2013. This meeting was originally scheduled for October 22-23, 2013 but was postponed "due to resource constraints arising from the government shutdown."

The July Draft Guidance provided recommendations to assist in designing early-phase clinical trials of cellular therapy ("CT") and gene therapy ("GT") products, collectively referred to as "CGT products", which covers most Phase 1 trials and some Phase 2 trials. FDA considers clinical study designs for CGT products to be different because of the way the products work and the potential for substantial risk. In the past, FDA halted CGT therapies due to experiences that included: (1) multiple-organ failure and death of a subject receiving a GT product for ornithine transcarbamylase deficiency, (2) late-onset T-cell leukemia in subjects who received a GT product for X-linked severe combined immunodeficiency, and (3) the development of tumors in the brain and spinal cord of a patient who received intrathecal allogenic stem cells for ataxia telangiectasia.

FDA's Guidance on early-phase clinical trials explained that unlike many small molecule drugs, there is much less experience across a broad population with CGT products, leading to more uncertainty with clinical study design and controls. Some CGT products persists in humans for an extended time period and the administration may involve surgery or other invasive procedures that may require use of an investigational medical device. Allogenic CT products, GT vectors, and proteins that may be produced by CGT products have the potential to produce an immune response that may produce an unintended adverse reaction or sensitivity to a CGT product in the future. CGT products are cellular products and so mimic the complex, dynamic nature of living cells, which can migrate within the recipient's body.

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December 10, 2013

Physical Attributes of Generic Tablets and Capsules Guidance Issued by FDA

troubleswallowingpills.pngOn December 9, 2013, FDA issued a new draft guidance: Size, Shape, and Other Physical Attributes of Generic Tablets and Capules. FDA said that it issued the guidance because it is concerned that patients perceive differences in the physical characteristics (e.g., size and shape of a tablet of capsule) of generic drugs in relation to its referenced listed drug ("RLD") counterpart. FDA believes that these perceived differences are "important" and "may affect patient compliance and acceptability of medication regimens or could lead to medication errors." FDA does not plan for the Guidance to apply to generic drugs that are already on the market, unless there are safety issues, or other oral dosage forms.

According to the Guidance, many individuals have difficulty swallowing tablets and capsules, perhaps as many as 40 percent of Americans. Of these individuals, most blamed the dosage form size as an issue. In some instances, the larger tablets or capsules have been "shown to prolong esophageal transit time," which may lead to disintegration of the product in the esophagus or cause injury to the esophagus, or more general adverse events such as pain, gagging, choking, and aspiration. In the industry, these larger tablets or capsules have been called "horse pills." Some tablet and capsule shapes are known to be easier to swallow and have faster esophageal transit times than similar dosage forms with the same weight, e.g., oval sizes are easier to swallow than round. In turn, patient compliance may be affected by the size and shape of a tablet or capsule. Other physical attributes that affect ease of swallowing include coatings, weight of the tablet or capsule, and surface area of the dosage form.

As a result, FDA recommends that as part of its quality initiatives for generic drug products, generic oral tablets and capsules should be of a similar size to their corresponding RLD. In particular:

  • If the RLD is less than or equal to 17 mm in it largest dimension, the generic product should be no more than 20 percent larger than the RLD in any single dimension (resulting dimention not to exceed 17 mm) and no more than 40 percent larger than the RLD in volume.
  • If the RLD is greater than 17 mm in its largest dimension, the generic product should be no larger than the RLD in any single dimension or volume.
  • We recommend the largest dimension of a tablet or capsule should not exceed 22 mm and that capsules should not exceed a standard 00 size
.

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December 5, 2013

Bioequivalence Guidance for ANDAs Released

FDA.bmpFDA issued a draft guidance Wednesday that provides its recommendations for generic-drug makers seeking to show bioequivalence to a reference listed drug. The document--Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA--does not represent a significant change or shift in FDA policy/opinion, but it covers many approaches and revises and replaces parts of two existing FDA Guidances (see here and here). And, most notably perhaps, the document is a consolidation of many of FDA's previous opinions and guidances on establishing bioequivalence that concludes with an attachment providing a summary of general approaches for the design and data handling of bioequivalence studies with pharmacokinetic endpoints. The document should provide would-be generic-drug applicants with a good starting place.

FDA's advice is very general, as the Agency states that companies should see FDA's product-specific guidances for information on individual drugs. But despite the lack of product-specific advice, the guidance provides significant detail about common study parameters. FDA starts with a general discussion of how best to establish bioequivalence. The Agency notes that applicants can establish bioequivalence using in vivo and/or in vitro methods, which include--in descending order of preference--pharmacokinetic, pharmacodynamic, clinical, and in vitro studies.

Regarding pharmacokinetic studies, FDA suggests that applicants use: (1) a two-period, two-sequence, two-treatment, single-dose, crossover-study design; (2) a single-dose-parallel-study design; or (3) a replicate-study design. To establish bioequivalence from the studies, FDA urges applicants to use the average bioequivalence method of analysis. The guidance provides that, if possible, the study population should consist of enough subjects--18 years and older and representative of the entire population, considering age, sex, and race--to provide adequate statistical power.

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October 8, 2013

Refuse-to-Receive ANDA Guidance Issued

refusetoreceive.pngOn September 30, 2013, before the federal government shut down hit, FDA published a new guidance, "ANDA Submissions-Refuse-to-Receive Standards". FDA's guidance explains many of the principles that have been articulated in FDA's "ANDA [Abbreviated New Drug Application] Checklist for Completeness and Acceptability of an Application" ("ANDA Checklist"), which is reviewed quarterly basis (calendar year) and updated on an "as needed" basis. The Guidance reported that refusal-to-receive decisions ("RTRs") "underscore the need for improvement in the quality of original ANDAs." Between 2009 and 2012, FDA's Office of Generic Drugs ("OGD") refused to receive 497 ANDAs, the Guidance explains. RTRs occurred with regard to original submissions, in 2009 - 12%; 2010 - 18%; 2011 - 15.5%, and 2012-9.4% (estimated). The most common reasons for RTRs included serious bioequivalence deficiencies and serious chemistry deficiencies, with other lead causes being format or organizational flaws, clinical deficiencies, and inadequate microbiology. As a result, FDA believes that it would help to clarify its RTR criteria to help improve ANDA quality.

First, FDA noted that as part of its threshold determination for filing, FDA reviews ANDAs following the ANDA Checklist, which is formatted to mirror the organization of the Electronic Common Technical Document ("eCTD"). As a matter of general policy, FDA will notify an applicant if it will issue a RTR and provide the applicant with the opportunity to withdraw its ANDA, amend to correct the deficiencies, or take no action. FDA intends to work with applicants if there are fewer than ten minor deficiencies, with such notification by phone, e-mail, or facsimile. If the applicant can correct the deficiencies within five business days and FDA so finds, then FDA will still receive the application from its original receipt date; if not so corrected, FDA will RTR the application. FDA will issue an RTR, however, if the application contains more than ten minor deficiencies or one or more major deficiencies.

The Guidance goes on to explain what FDA considers major deficiencies: failure to submit a completed FDA Form 356h, organizational/format failures, non-payment of Generic Drug User Fee Act payment obligations, lack of a U.S. agent for a foreign applicant, failure to provide an environmental assessment (or claim of categorical exclusion), failure to ensure the proposed labeling is consistent with the filed patent statement (i.e., the proposed method of use, with one exception where a patent is listed but the referenced listed drug ("RLD") does not include the claimed use (Here, OGD will advise if this approach was correct or if the labeling or patent statement need revision.), citing an incorrect or unfounded basis of submission, other labeling deficiencies (not electronic or not the same as the RLD with not appropriate explanation for certain allowed differences such as change of manufacturer name), drug master file deficiencies, chemistry deficiencies, and bioequivalence and clinical deficiencies. Where an applicant has questions, FDA encourages Control Correspondence for guidance, with the exception that applicants are to consult product-specific bioequivalence recommendations rather than sending FDA Control Correspondence except for further guidance to explain the public guidance. FDA will consider alternative bioequivalence or other criteria in some instances with adequate justification, the Guidance further explains.

As more GDUFA measures are implemented over time, as with this one, it will be interesting to see if FDA will report improved ANDA quality or if the problems persist.

September 16, 2013

Animal Food Additive Petition Guidance Issued by FDA

compound feed.pngOn September 11, 2013, FDA issued a draft Guidance entitled, "Recommendations for Preparation and Submission of Animal Food Additive Petitions." This Guidance provides the Center for Veterinary Medicine's ("CVM's") recommendations regarding information to be included in food additive petitions ("FAPs") for animal foods. FDA regulates food and substances added to food, some of which are "food additives."

A food additive is:

any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component of or otherwise affecting the characteristics of any food, unless the substance in Generally Recognized as Safe (GRAS) among qualified experts under the conditions of its intended use, or meets one of the other exemptions to the food additive definition (e.g., new animal drug, color additive, etc.).

To use a food additive in animal food, the additive must first be approved by FDA for such use. The Federal Food, Drug, and Cosmetic Act ("FD&C Act") sets forth a petition process to ensure that the use of a food additive in animal food is safe. The process is set forth in section 409 of the FD&C Act. Prior to initiating a petition, applicants should verify whether the additive is already approved, i.e., there is a regulation in place for the intended use of the substance in animal food.

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April 1, 2013

Biosimilar Meeting Guidance Issued by FDA

dna.jpgOn April 1, FDA issued a Federal Register Notice announcing a new draft biosimilars guidance, "Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants". This is the latest in FDA's new biosimilar guidances for 2013, which FDA has announced in earlier meetings this year would be coming to help spur the filing of a biosimilars application, which FDA has called 351(k) applications based on the section in the Public Health Service Act ("PHS Act"). As of a few weeks ago at the Massachusetts Biotechnology Association's ("MassBio's") Annual Meeting, which we blogged on here, FDA's Commissioner, Margaret A. Hamburg, M.D., continued to report that FDA has not received a single 351(k) application to date.

The Guidance focuses on formal meetings for 351(k) applications and the associated requirements or performance goals from the Biosimilar User Fee Act of 2012 ("BsUFA"), which was enacted as part of the Food and Drug Administration Safety and Innovation Act ("FDASIA"). In particular, the Guidance discusses the principles of good meeting management practices ("GMMPs") and describes standardized procedures for requesting, preparing, scheduling, conducting, and documenting such formal meetings.

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March 6, 2013

Medical Device Communication Draft Guidance Issued

communicate.jpgOn March 5, FDA issued a new draft guidance, "Types of Communication During the Review of Medical Device Submissions." During the development of the various medical device user fee amendments ("MDUFA"), the discussion of improving communications between device applicants and FDA was suggested, described as an Interactive Review. The collection of additional funds from MDUFA-related activities will enable FDA to improve the device review process and help meet certain performance goals incorporated into MDUFA. Some of the suggested communications included Acceptance Review, Substantive Interactions, Interactive Review, and, where applicable, Missed MDUFA Goals.

The purpose of Acceptance Review communications are to: (1) identify the lead reviewer or Regulatory Project Manager assigned to the submission and (2) confirm acceptance of the submission or notify the submitter that the submission was not accepted based upon the review of objective acceptance criteria. FDA aims to make these communications within 15 days of receipt of a 510(k), original premarket approval application ("PMA"), or a Panel-Track PMA Supplement, with such confirmation by fax, e-mail, or other written communication.

Substantive Interactions tell applicants that FDA either: (1) intends to continue working with the applicant to resolve any outstanding deficiencies (no hold), or (2) FDA has identified deficiencies sufficient to place the submission on hold. Substantive Interactions should occur following acceptance of the submission and only after FDA has performed a complete review with targets of within 60 days of receipt of a complete 510(k) or within 90 days of the filing date of an original PMA, Panel-Track PMA Supplement, or 180-Day PMA Supplement.

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February 11, 2013

Early-Stage Alzheimer's Disease Drug Development Draft Guidance Issued by FDA

alheimers.jpgOn February 5, 2013, FDA announced the availability of Draft Guidance relating to the development of drugs for the treatment of early stage Alzheimer's disease. The Draft Guidance, titled, "Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage Disease" addresses: (1) diagnostic criteria for early stage Alzheimer's disease; (2) appropriate clinical outcome measures; and (3) ways to demonstrate disease modification. Addressing these issues in early stage Alzheimer's disease poses unique difficulties, because patients may have little to no impairment of global functioning. FDA is seeking public comment on the Draft Guidance within sixty days.

The Draft Guidance provides FDA's current thinking on useful diagnostic criteria for early Alzheimer's disease. FDA cited useful research in developing diagnostic criteria, such as the research criteria for prodromal Alzheimer's disease and preclinical Alzheimer's disease. Specifically, FDA also cited as useful efforts by the research community to incorporate biomarkers into the diagnostic criteria. FDA concluded that, "we support the concept of enriching trial populations with patients most likely to progress to more overt dementia, using both clinical biomarker-based criteria." FDA also indicated, however, that FDA could not formally endorse any specific diagnostic framework, because more work was necessary to assess the specificity and sensitivity of these criteria, as well as the validation of these methodologies.

The Draft Guidance also provides FDA's current thinking on ways to establish clinical efficacy in trials involving patients suffering from early stage Alzheimer's disease. While FDA requires a co-primary outcome measure to demonstrate efficacy on both cognitive and functional levels for clinical trials on the dementia stage of Alzheimer's disease, in the draft guidance, FDA acknowledged that these endpoints may be impractical for patients suffering from early stage disease. Therefore, FDA indicated that for early stage disease "clear evidence of an effect on delaying cognitive impairment may provide sufficient evidence of effectiveness."

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January 23, 2013

Combination Product Final Rule and Guidance Issued to Streamline CGMP and Supplements

Thumbnail image for 3699948229_d7732f8df0_o.jpgYesterday, FDA issued two new items to help clarify combination products: 1) a Final Rule published in the Federal Register entitled, "Current Good Manufacturing Practice Requirements for Combination Products" and 2) a Draft Guidance entitled, "Guidance for Industry and FDA Staff:
Submissions for Postapproval Modifications to a Combination Product Approved Under a BLA, NDA, or PMA", also announced in the Federal Register.

The Final Rule is intended to clarify which good manufacturing practice ("CGMP") requirements apply when drugs, devices, and biological products are combined to create combination products. The Rule also provides a mechanism that FDA describes as "transparent and streamlined regulatory framework" for companies to use when demonstrating compliance with CGMP requirements for "single-entity" and "co-packaged" combination products. "Single-entity" combination products are two or more regulated components, e.g., drug/device, biologic/device, drug/biologic/device, which are physically, chemically, or otherwise combined or mixed and produced as a single-entity. Two or more separate products packaged together in a single package or as a unit and comprised of two or more regulated products is a "co-packaged" combination product. The Final Rules started as a Draft Guidance announced on October 4, 2004 (69 FR 59239), entitled "Current Good Manufacturing Practices for Combination Products." Based on comments and FDA's own internal review, FDA decided that "rulemaking was warranted" and issued Proposed Rules on September 23, 2009 (74 FR 48423).

The concept behind the CGMP Rule is simple for parts that are separately manufactured and marketed: each of the constituent parts of a combination product are subject only to the CGMP regulations applicable to that part, e.g., drug, biologic, or device. The two categories of combination products mentioned above, however, "single-entity" and "co-packaged" are slightly different due to the possibility for overlapping CGMP requirements for the different regulated components. Companies have two basic options for these types of products: 1) demonstrate compliance with the specifics of all CGMPs to each of the parts, or 2) demonstrate compliance with the specifics of either the drug CGMPs at 21 C.F.R. Parts 210 and 211 or the quality system ("QS") regulation at 21 C.F.R. Part 820 rather than both, for drug/devices under certain conditions. For combination products including biologics, the specific regulations are 21 C.F.R. parts 600 through 680, and for product including any human cell, tissue, and cellular tissue-based products, the regulations are 21 C.F.R. Part 1271.

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January 4, 2013

Safety Reporting Requirements Explained -- More Targeted Reporting Emphasized

3699948229_d7732f8df0_o.jpgTowards the end of last year, FDA added two new final guidances related to the safety reporting requirements for investigational new drug exemptions ("INDs") and bioavailability and bioequivalence ("BA/BE") studies entitled: Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies and Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies-Small Entity Compliance Guide. These guidances are intended to explain final rules published on September 29, 2010 that amended the IND safety reporting requirements under 21 C.F.R. Part 312 and added safety reporting requirements for individuals conducting BA/BE studies under 21 C.F.R. Part 320. We blogged on that development then.

A key focus of the new regulations was to add clarifying definitions to certain terms, "adverse event", "suspected adverse reaction", "unexpected" adverse event or reaction, "serious" adverse event or reaction, and "life-threatening", as well as further define reporting requirements. According to the main Guidance (not the one for small entities), sponsors frequently took a broad reading of the phrase "associated with the use of the drug" in the context of the former 21 C.F.R. § 312.32(a), which stated, "there is a reasonable possibility that the experience may have been caused by the drug." With this broad reading, the Guidance continues, "sponsors frequently reported, as individual cases, serious adverse experiences for which there was little reason to believe that the drug caused the event." The Guidance includes three examples of overzealous reporting, including reporting adverse experiences that were manifestations of the underlying disease, common occurrences in the study population independent of drug exposure, or study endpoints. FDA described these types of reporting as a drain on agency resources and "uninformative when reported as single events (i.e., without a comparison of the incidence of the event in treated and untreated subjects), they do not contribute meaningfully to the developing safety profile of an investigational drug or to human subject protection."

Interestingly, this appears to be somewhat of a departure from how FDA had enforced its reporting regulations on clinical investigators. Shortly after I first joined FDA in the 1990s, I was involved in a clinical investigator disqualification proceeding that resulted in a clinical investor being disqualified from further clinical studies because, among other things, he had not timely or accurately reported certain adverse events. While the Presiding Officer took into account that many of the patients had underlying conditions prior to the experimental therapy, the Center for Drug Evaluation and Research ("CDER's") approach appeared to focus on the need for the investigator to report all adverse event associated with the therapy. In this case, the therapy had to do with infusing a drug with a catheter to help dissolve gall bladder and common bile duct stones, which the CDER described as a drug/device. The investigator admitted that he had not immediately reported certain events that occurred as a result of the catheter insertion (most likely not due to the drug) or the patient's underlying conditions, because in his opinion, they were not associated with the drug therapy. At that time, CDER took the approach that the investigator's opinion was irrelevant, because the adverse events were at least temporally associated with the drug/device and therefore had to be timely reported.

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December 6, 2012

Electronic Clinical Source Data Draft Guidance Published by FDA

On November 19, 2012, FDA issued a draft Guidance entitled, "Electronic Source Data in Clinical Investigations." The Guidance recommends various procedures relating to the electronic capture of source data in clinical investigations in an effort to reduce errors, to provide real-time data access, and to maintain accurate records for inspection by study investigators and FDA.

Clinical Data Guidance

Source data includes all information found in original clinical investigation documents (or certified copies of original documents) and this information is used for the reconstruction and evaluation of clinical trials. Accurate transcription of source data is extremely important, and the Guidance discusses methods of identifying source data, creating easy identification methods for auditing, capturing source data, and reviewing and retaining the data. The Guidance discusses the identification of source data originators, the capture of source data, the creation of data element identifiers, and the investigator's duty to review and retain electronic data.

The Guidance focuses on data entered into electronic case report forms ("eCRFs"). An eCRF is an electronic record, created for all clinical study subjects, that is reported to the study sponsor as per the study protocol. eCRFs contain data elements that are entered into the system by data originators such as investigators, medical devices, and clinical investigation subjects. Data elements are the smallest units of observation made during a clinical investigation and they include observations such as weight, birth date, race, or body temperature. The Guidance recommends that each sponsor and investigator maintain a list of data originators (e.g., people and devices) authorized to enter data elements for each study protocol. These lists limit access to data entry by creating unique user names, passwords, and identifications and by setting time periods for when each data originator can enter data.

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October 18, 2012

European Biosimilars to Reference Non-European Biosimilars

Thumbnail image for Thumbnail image for dna.jpgWhenever an applicant wishes to register their follow-on medicinal product, be it a generic product or a biosimilar, the applicant has to include in their dossier a comparison between the newly-developed product with a previously-approved and registered medicine. For "standard" generic products evidence, such as the approved product's dosage form, strength, excipient and content can be obtained from published information and further "proof" is generated by such things as dissolution profiling and bioequivalence studies. However, there is always a question as to whether the comparison product (usually the originator's product) is the same internationally. For example, it is possible that the same active ingredient in the same dosage form could have been formulated differently from country to country, either as a result of differing timing of the drug's development and launch or on purpose to create artificial barriers, such that the follow on products will be more complex to develop. Of course, the difficulty of having what outwardly appears to be the same product, but inwardly is significantly different, creates potentially dangerous problems for both doctors and patients. Clearly, if a patient travels across borders and needs to refill their prescription, it could result in real problems, if the apparent same drug and dosage form act differently biologically.

Health authorities around the world now work much more closely together and confidential information about their registered and approved products can be passed between them, such that differences in formulations that affect bioavailability would be available to them and thus will be alert to possible issues. For a company making a follow-on product, however, this information is not available. As a result, companies wishing to make a generic product have to carry out extra studies as outlined above to investigate the differences from country to country and carry out bioequivalence studies against a local reference product.

Biological medicines are medicines that are made by or derived from a biological source. They can consist of relatively small molecules, such as human insulin or erythropoietin, or complex molecules, such as monoclonal antibodies. Biosimilar products are, thus, far more complex and need far more studies to show similarity, requiring a large number of clinical trials, as opposed to the bioequivalence studies that generic products undergo. Given the difficulty in developing, testing and registering new biological, it may well be that, unlike non-biological medicines, biological products may well be the same product internationally.

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