Biopharmaceuticals: A Lack of Authoritative Product Information Prevails

    As disucussed elsewhere, biopharmaceuticals are defined and regulated as distinct products based on their unique identity/source, manufacture and specifications (process = product), with approvals being secret (not publicly disclosed) pacts between the manufacturer and regulatory agency regarding the standards/specifications for the processes and product at each stage of manufacture. By these standards, almost nothing of substance is known about most biopharmaceutical products!

    Biopharmaceuticals are the most technologically advanced of all products. You would think innovators and biogeneric developers would want to proudly proclaim their achievements. Yet, developers and manufacturers uniformly refuse and designated public information gatekeepers are utterly paranoid about disclosures of any substantive information, other than regarding the products' medical/use and, sometimes, business-related aspects. Manufacturing information and specifications, even generalized nonenabling descriptions, are rarely publicly disclosed or available from manufacturers, marketers or regulators.

    The only public information gatekeepers in most companies are the public/investor/press relations and medical information departments. PR/press contacts uniformly state (and believe) that anything to do with products other than medical/use and sometimes sales and other business information (depending on the size of the company), is proprietary and not disclosable. This includes any all information about products (beyond the product insert). PR reps commonly even refuse to disclose information in prior press releases; refuse to send or contact staff to request they send copies of publications, even where the company has received related awards; etc. Common scientific community courtesy and access to published information, e.g., reprint requests, are alien to PR/press offices, which express paranoia or freeze-up (usually, start acting ignorant, repeating questions, etc.), if your interests involve non-medical product-specific information. Many PR reps agree that this is simply the prevailing corporate culture, with PR offices only able to refer inquiries they cannot handle to the medical information department.

    Medical information departments, usually the only corporate public information gatekeepers in most biopharmaceutical companies besides the PR/press relations department, almost uniformly have been stripped of product-related information other than that strictly concerning medical and use aspects. Even staff publications of interest concerning product development and, particularly, manufacture, are not kept in their database/collections or otherwise known to them. Most medical information departments often have no technical information available about their products, and their staff often concede that they, themselves, are ignorant about what their products are in any technical sense - how they are manufactured, minimum specifications met, etc. Product bibliographies often do not include any references concerning these technical aspects of products.

    Other than the manufacturer/marketer, the only other authoritative source for product information is regulatory agencies (which recycle information from the manufacturer). In recent years, CBER/FDA public documents and discussions rarely even mention manufacture, specifications, CMC aspects, etc. Anyone reviewing public product approval documentation, e.g., at the CBER/FDA Web site, would conclude that CMC aspects are not important to approvals, since they are rarely even mentioned, much less described or discussed. Very often, the only truly authoritative descriptive information regarding products is in product inserts/labeling, usually just a few sentences at best; with review documents, advisory committee briefing documents, etc., very often never defining or describing at all what a product is, usually simply referring to it by its FDA proper (internal generic) or trade name.

    Many have remarked that the European Union (EMEA) is less transparent regarding access to information than the U.S. (FDA). However, European Product Assessment Reports (EPARs), documents that review and justify product approvals, are now much more informative than any from FDA. For example, these often include discussions of significant changes in manufacturing (i.e., the product) during development and testing, while FDA documents fail to mention this and other critical information relevant to understanding the product, including the validity of results from clinical trials using essentially different (but comparable) products.

    With no real (substantive and authoritative) information available concerning current biopharmaceuticals, how can there be meaningful public oversight or discussion of biogenerics? Will the situation change with the advent of biogenerics? Will biogeneric manufacturers disclose or will approvals include even general discussion of manufacturing aspects and the similarties with innovator products? Will biogeneric manufacturers recognize that it is in their self-interests to disclose public information, to prove that their products are similar and reliably safe and effective, or will they stonewall and simply point to regulatory approvals as validation of their products? Similarly, will innovators realize that it is in their self-interests to disclose manufacturing, specifications and other substantive information concerning their long-established products, if only as a defensive measure to raise the standards and expectations biogenerics will have to meet?

    Regulatory Agencies Fail to Provide Needed Information

    Regulatory approvals and information often are of little help and often only confound identifying and naming specific biopharmaceutical active ingredients and finished products. The product registries, approval listings, etc., publicly available from FDA and other regulatory agencies generally poorly and inadequately identify, differentiate between or describe similar biopharmaceutical products. Many regulatory agencies primarily identify products by adopting nonproprietary names, e.g,, CBER/FDA proper names for biologics, which are generic and describe a class rather than specific products; and as needed, sometimes link these names with a trade name (trademark) or add modifiers, e.g, alfa, beta, to differentiate products based on order of approval. These FDA and other regulatory agency names adopted for products are often nonproprietary names, e.g., USAN or INN. The underlying nature of regulatory approvals confounds assignment of unique and unambiguous names or disclosure of even the most basic descriptive information for biopharmaceuticals, especially for all but the simplest biopharmaceuticals, e.g. those regulated by FDA as biologics.

    Biopharmaceutical approvals, particularly for biologics, are essentially secret pacts between the regulatory agency and the manufacturer, with the product defined as meeting an agreed upon set ranges of variations in processing and specifications (CMC aspects; process=product-related variables). Only the sponsor and regulatory agencies ever really know what the product is (in the process=product context). Often, the only truly authoritative statement about what a product is is contained in a few sentences in its product insert or labeling. To make the situation worse, most supplemental approvals, particularly those involving manufacturing changes, are hardly ever even publicly disclosed, much less useful information disclosed about process and product modifications. Thus, all publicly available descriptions and information about biopharmaceuticals should be recognized as inherently incomplete and, perhaps, dated.

    Product-related information is presented in volumes of chemistry, manufacturing and quality control data, procedures, in-process and other standards, etc., submitted by the sponsor. However, even brief summaries of obvious nonproprietary information, including that published by the sponsor, are almost never publicly disclosed. Nearly all FDA public approval review documentation, including FDA Summary Basis of Approval (SBA)-type documents and public advisory committee meeting briefings and minutes, fail to discuss or even summarize obviously nonproprietary information about products' processing and specifications. In fact, it is very common to review FDA public documentation regarding approved biologics and not find any information at all that identifies or describes the active agent and finished product, beyond referring to it by a proper name and/or trademark, often without even a one or two line description of the active agent and formulation. It is often unclear what has been approved. This nondisclosure of even the most basic descriptive information or defining the product having received approval is even the case with critically important information relevant to judging product safety. This includes different products (e.g,. manufactured using a different cell line or by a different, e.g., contract, manufacturer, having a different formulation or physical state, e.g., liquid vs. lyophilized powder) publicly known to have been used in clinical trials and other testing during different stages of development. In fact, substantive product identification and descriptive information is so scant that one could conclude from available documentation that chemistry, manufacturing and control (CMC) and GMP issues are no longer a part of biologics approvals. Thus, other than clinical testing and related safety studies, in terms of even the most basic, minimal product identification and descriptions that would assist in defining and differentiating biologics, CBER/FDA is a black hole, with no light ever coming out, much less illuminating approved products.

    Nearly all FDA public approval review documentation, such as FDA Summary Basis of Approval (SBA)-type documents and public advisory committee meeting minutes, fails to discuss or even summarize obviously nonproprietary information about products' processing and specifications. For example, FDA approval/review-related public documents often fail to even mention a recombinant proteins expression system, identify the establishment that manufactures the product, etc., while often going into incredible detail about clinical trials. Similarly, any such relevant information, often including information that has been published and is well-known to anyone with any familiarity at all with the product, is redacted (censored) from FOI and other public document disclosures. In fact, it is very common to review FDA public documentation regarding approved biopharmaceuticals, particularly biologics, and not find any information at all that identifies or describes the active agent and finished product beyond referring to it by proper name and/or trademark and maybe a one or two line description of the active agent and formulation. This nondisclosure of even the most basic descriptive information or defining the product having received approval is even the case where critically important information disclosed elsewhere is not disclosed or even mentioned. This includes different products (e.g,. manufactured using a different cell line or by a different, e.g., contract, manufacturer, having a different formulation or physical state, e.g., liquid vs. lyophilized powder) are publicly known to have been used in clinical trials and other testing during different stages of development. One would presume that such information is critical to interpreting clinical, toxicological and other studies routinely discussed in incredible detail in the same public review-related documents. In fact, descriptive product information is so scant such that from review of FDA biologics public documentation, one would conclude that chemistry, manufacturing and control (CMC) and GMP issues are no longer a part of biologics approvals. There are often not even boilerplate statements that the product's manufacture meets GMP standards. In these respects related to the most basic, minimal identification of what has been approved and, ideally, providing some brief description of the active ingredient and finish product, EMEA/EU European Public Assessment Reports (EPAR) documents are now generally much more informative than anything coming from FDA. In fact, particularly in the biologics area, FDA obviously goes out of its way not to disclose or be recognized as a source for product-related information. Thus, in terms of even the most basic, minimal product identification and descriptions that would assist in defining and differentiating biologics, CBER/FDA is a black hole. The agency receives masses of information from sponsors, and releases in-depth reviews of clinical and other safety and efficacy-related studies submitted by the sponsor, but often even fails to identify or describe the product, much less its manufacture and specifications, beyond referring to it by its proper (a generic, nonspecific) and/or trade name (trademark).

    Are manufacturers/marketers a useful source for product information?

    Generally, no! -- Unless your interest is in medical (use) or company information. The information gatekeepers (e.g., public relations and medical information departments) fail or refuse to provide substantive product information. There is a prevalent assumption (misconception) in industry, particularly among the larger and more established companies, that all product (vs. medical/use) information is proprietary, even including information previously disclosed, published and hyped by the company in press releases. The databases and literature collections of many, particularly the larger, company medical information departments have been scrubbed of all references to descriptive product information (concerning chemistry/indentity, manufacture, quality control). This is often to such an extent that these offices freely admit not knowing what their own biopharmaceutical products are (beyond the scant information in product inserts/labeling) -- allowing 'plausible denial' based on corporate ignorance. The (bio)pharmaceutical industry has obviously not (re)examined its policies for disclosure of substantive product information for decades. Often larger companies have no idea of what information is available in-house, e.g., there have been cases where product managers and company contacts have stated emphatically that no product monograph is or has ever available, while this author has a copy in hand previously obtained from the company.

    The most common response from company PR/press offices requested to provide "readily available, public domain, e.g., published, information" about their products is simply crude/rude neglect (i.e., no response, not even to written requests following-up phone contacts), while considerable high quality medical/use information is readily available. They apparently hope the technically-oriented requestor will simply go away. When written inquiries are followed up by phone, company spokespersons, including Ph.D's, commonly revert to acting ignorant -- acting as though they don't understand the request, as though such a request (for descriptive product vs. medical information) is totally unprecedented/unheard-of, and/or they repeat overly simplistic questions -- effectively halting communication. Some companies have even refused to provide product inserts, promotional literature, prior press releases, etc., once they determine one's primary interest is in the product vs. medical/use information. One company, when asked if staff scientists could be contacted to request reprints of their product-related publications, remarked that this would viewed as "guerrilla warfare" against the company.

    What about product inserts/labeling? These are often the only truly authoritative information source available! However, these are prepared for physicians and health care delivery professionals and contain minimal information about the chemistry/identity, manufacture and specifications/quality control of the product. Even purchasers of nutraceutical, nutritional supplements and other types of products often receive or have available more substantive/descriptive information than is available regarding many biopharmaceutical products (which is all the more reason to use Biopharmaceutical Products in the U.S. and European Markets, which cumulates information from 1000s of sources collected over an 8-year period).