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Adverse Events with New Chemical Entities, Generics, Excipients, Placebos, and Counterfeits

Are some adverse events (AEs) created more equal than others? Are some AEs more important than others? Why AEs with generics and older drugs are important. What to do with other manufacturers’ AEs. Why AEs with new chemical entities are critically important. Why AEs due to excipients are so hard to pick up. Why AEs with over-the-counter drugs are also important. Why AEs before taking the drug can matter.

The reporting requirements for AEs and drugs are generally thought of as being critical for the safety evaluation of new chemical entities (NCEs), also called new molecular entities (NMEs), newly approved for marketing. NCEs, by definition, have not been on the market before. Their safety profile is known only from limited laboratory, animal, and human testing under an IND or equivalent. Clearly, AE reporting is critical in this period, and companies and agencies pay particular attention to the spontaneous AE reports received shortly after launch (known as the Weber effect: a large number of AEs/ADRs reported just after launch that decrease after some months to a lower, more steady-state number of reports). Rare AEs that were not seen in the trials are often picked up in the weeks to months after launch in major markets with good AE reporting structures, such as the United States or Europe. Regulations on AE reporting are written with this in mind.

Given the large number of AEs that drugs can produce and given the limited number of resources that health agencies, companies, and healthcare professionals can devote to reporting and processing AEs, there is an ongoing debate about what AEs are most cost-effective and medically important to collect to protect the public health. Much work is under way to either improve or add to the spontaneous reporting systems in use throughout the world. The FDA MedWatch program collects safety information about prescription and over-the-counter drugs, biologics, medical and radiation-emitting devices, and special nutritional products (e.g., medical foods, dietary supplements, and infant formulas). See the FDA’s website (Web Resource 5-1). Health Canada has a similar system known as MedEffect (Web Resource 5-2). The United Kingdom’s MHRA has a system known as the Yellow Card system, dating back to when yellow handwritten cards were used to submit AEs (Web Resource 5-3). The French system is described in French on the website of the French Health Authority (Web Resource 5-4). Many other countries have their systems described and available online on the health authority’s website.

The current regulations from the FDA do not address generics. Any drug under an NDA or an ANDA must meet the AE reporting requirements in 21CFR314.80. This includes generics and NCEs. In the European Union, a similar requirement for generic pharmacovigilance is noted in Volume 9A:

If the manufacturer of a branded product receives an AE from a generic version of its product, it should database the AE and report it, as appropriate, as an expedited report or in the periodic report, noting that it is the generic and not the company’s branded drug. If the manufacturer of the generic is known, the branded company should still database the event and may or may not send a copy of the event to the manufacturer of the generic. Volume 9A (Section 4.1. page 56) states:

Most other countries have similar requirements for generic drug safety reporting.

An excipient is a theoretically inactive ingredient added to a drug to provide bulk or to give it form or consistency. In regard to excipients, there are many types, including binders, fillers, diluents, lubricants, sweeteners, preservatives, flavors, printing inks, colors, and others. The most common ones used in the United States include magnesium stearate, lactose, microcrystalline cellulose, silicon dioxide, titanium dioxide, stearic acid, sodium starch glycolate, gelatin, talc, sucrose, povidone, pregelatinized starch, hydroxyl propyl methylcellulose, shellac, calcium phosphate (dibasic), and others. Standards are set by committees of the United States Pharmacopeial Convention and published in the United States Pharmacopeia and the National Formulary.

Excipients became a major issue in the United States when a sulfonamide elixir was diluted in diethylene glycol (automobile antifreeze) and killed about 100 Americans, including children. It led in 1938 to the Food, Drug, and Cosmetic Act. An excipient for drugs is approved for use in the United States by one of three mechanisms:

1. It meets the requirements of being “Generally Recognized as Safe” under 21CFR182, 184, 186.
   
2. The FDA approves a petition as a food additive under 21CFR171.
   
3. It is referenced in an approved NDA for a particular function for that drug.

Excipients for over-the-counter products must comply with section 21CFR330.1(e) as “safe in the amounts administered and do not interfere with the effectiveness of the preparation.”

Please refer to the excellent website run by the International Pharmaceutical Excipients Council (Web Resource 5-5) for further information.

The FDA definition of an adverse drug experience refers to “any AE associated with the use of a drug” (21CFR314.80a)) without indicating whether the event is associated with the active ingredient (moiety) or an excipient. Should the submitter have some reason to suspect an excipient to be the cause of the AE, this should be noted in the report and the appropriate investigations and follow-up done. Note that the FDA has revised its definitions for pre-marketing AEs (21CFR312) and is expected to do the same for the postmarketing definitions based on ICH and the proposed FDA regulations (“The Tome”).

The ICH document Q8 describes in detail how excipients are handled in pharmaceuticals. See ICH’s website for the document (Web Resource 5-6).

In the European Union, Volume 9A only refers to excipients in regard to altering PSUR cycles. There is no direct comment on AEs possibly related to fillers or excipients. Excipients in one country may be considered active ingredients in other countries and vice versa. As in the United States, the European Union, and elsewhere, Good Manufacturing Practices have detailed regulations and guidelines on excipients.

In general, most countries require Quality Management systems and life cycle risk management for all products. Under this general heading, excipients are included. Thus, if a signal or safety issue should arise regarding an excipient, this is expected to be handled expeditiously. Most regulations require safety reporting for the entire product, not just the active moiety. Thus, adverse events seen with the drug product, whether due presumably to the active ingredient or an excipient, must be handled in the same way as expedited reports or periodic reports as required by regulation and law. The trick is to distinguish an AE due to an excipient rather than the active ingredient. If the former, the problem should be rectifiable, if the latter, then the event is a pharmacologic property of the drug and unlikely to be diminished with manufacturing changes.

As placebos are rarely used explicitly in clinical practice, this refers only to clinical trials. All AEs (whether to active drug, comparator, or placebo) must be captured and databased. The only issue is expedited reporting of placebo events.

In the United States, placebo AEs from trials do not generally have to be reported as expedited reports. However, many blinded trials do have AEs (including serious AEs) reported as blinded events during the trial either as expedited reports or in periodic or annual reports. At the end of the study, the unblinding reveals some of them to be associated with placebo and not active drugs. In addition, in preparing final study reports, integrated safety sections for NDAs, dossiers for marketing approval in the European Union and elsewhere, and comparisons of AEs on active drug and placebo must be reported if there is a placebo arm of the trial. Thus, all placebo AEs should be recorded and tracked in the safety database.

In the European Union, some countries require reporting of all AEs related to the “biomedical research,” not just to taking the active study drug. In this case, placebo cases need to be reported as expedited reports and in periodic summary reports. The European Union Clinical Trial Directive (2001/20/EC of April 4, 2001) defines an “investigational medicinal product” as “a pharmaceutical form of an active substance or placebo being tested or used in a clinical trial” and requires certain serious AEs to be reported as expedited reports. Some have read this to mean a requirement for placebo reporting. Volume 9A does not expressly address placebo reporting. In the United Kingdom, the “Clinical Trials Toolkit” from the United Kingdom Department of Health/Medical Research Council (Web Resource 5-7) states:

The Good Pharmacovigilance Practice Guide (MHRA Pharmaceutical Press, London, 2009, www.pharmapress.com), from the MHRA, also notes:

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