10

Children, Elderly, and Other Special (Vulnerable) Groups

Similar to the testing of new drugs in pregnant women, the testing of drugs in special (“vulnerable”) groups poses issues. Special groups include children, neonates, and the elderly as well as other groups with specific disease states, genetic conditions, and, sometimes controversially, various ethnic, racial, or religious backgrounds. The question here is whether the presence of the “special” condition alters the effects of the drug and produces more or different adverse events (AEs).

Children

Children are a special group because they are not simply “small adults” but rather are (depending on age and other factors) biologic beings who absorb, distribute, metabolize, and excrete drugs differently from adults.

A key document on pediatric drug development is the International Conference on Harmonization (ICH) E11 “Guidance on Clinical Investigation of Medicinal Products in the Pediatric Population,” which can be found at Web Resource 10-1. This guidance notes in regard to safety that children differ from adults in having still-developing body systems and that additional considerations may be involved.

The guidance also addresses the definition of a “child,” noting the following possible categories and describing the issues in safety and efficacy of each:

• Preterm newborn infants
  
• Term newborn infants (0–27 days)
  
• Infants and toddlers (28 days to 23 months)
  
• Children (2–11 years)
  
• Adolescents (12–16 or–18 years, depending on region)

In the United States

In the United States, the FDA has been encouraging pediatric pharmaceutical research by companies for many years, but these efforts generally met with little success because of the hesitancy to test new chemical entities in children and babies.

In December 1998, the FDA issued a final rule entitled “Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients,” which is available at Web Resource 10-2. This rule required that every new product contain a pediatric assessment or a deferral or waiver of this assessment. It also allowed the FDA to require pediatric studies and required a pediatric section in New Drug Application (NDA) periodic reports.

In September 1999, the FDA issued a Guidance for Industry entitled “Qualifying for Pediatric Exclusivity Under Section 505A of the Food, Drug and Cosmetic Act,” which is available at Web Resource 10-3. This guidance allowed the FDA to request, before approval of a drug, that pediatric clinical trials be done. As an industry incentive to do this, a 6-month additional period of “exclusivity” (patent protection) could be granted. This was followed up by additional FDA actions, including a draft guidance in 2000 on pediatric oncology studies, and other guidances on complying with this rule, including one in 2000 on complying with the Pediatric Rule (21 CFR314.55(a) and 601.27(a). See Web Resource 10-4.

However, major changes occurred with the 2007 PDUFA/FDAAA legislation. Two sections of the FDA Amendments Act (entitled the Pediatric Research Equity Act (PREA) concerned children:

• Title IV reaffirmed FDA’s authority to require a manufacturer to submit an NDA for a new chemical entity, indication, dosage form, dosing regimen, or route of administration to submit a pediatric assessment. Sponsors may be given waivers from this for appropriate reasons (e.g., no pediatric formulation).
  
• Title V allows FDA to give an additional 6 months of marketing exclusivity to a manufacturer of a drug who submits data on pediatric use.

An internal FDA review committee was established in 2007 and has been meeting frequently and issuing reviews, assessments, and label changes and has requested various studies. A Pediatric Advisory Committee (Web Resource 10-5) has issued many product-specific safety reviews (see Web Resource 10-6). Labeling changes for safety that relate to children are available at Web Resource 10-7.

There has been much discussion and movement regarding pediatric safety and labeling. One major area of controversy revolved around the use of cough and cold products (usually over-the-counter, or OTC) in children, especially young children. After much discussion, FDA and the manufacturers agreed on a labeling change, noting that the products should not be used in children younger than 4 years of age. New measuring devices and child proof packaging changes were also introduced. See Web Resource 10-8.

Another area that has produced and continues to produce controversy is the use of psychiatric drugs in children. In particular, the FDA has issued an advisory about the use of selective serotonin reuptake inhibitors (SSRIs) and suicidality, notably about their use in children and adolescents. See Web Resource 10-9. A similar advisory was issued by the European Medicines Agency (EMA) (Web Resource 10-10).

In the European Union

New legislation, Regulation (EC) No 1901/2006 (see Web Resource 10-11), covering children aged 0 to 17 years was passed in 2007.

The key elements of the legislation include:

• Creation of a Pediatric Committee in the EMA.
  
• A requirement for pediatric data based on a Pediatric Investigation Plan (PIP) for new products and certain products already on the market and still under patent. If this is done,
  
  
  
  • An additional 6 months of patent protection may be granted for “regular” products and a 2-year extension for orphan products.
    
  • A new Marketing Authorization (called the pediatric use marketing authorization) may be granted, giving a 10-year period of market protection.
  
  
• A European database of pediatric clinical trials is to be created.
  
• Data from pediatric clinical trials must be submitted to the regulatory authorities.
  
• A European Pediatric Clinical Trials Network was set up along with new funding for off-patent drug studies.
  
• Use of an identifying symbol on the package of all products approved for children.

For further information see the EMA website (Web Resource 10-12) and the MHRA website (Web Resource 10-13). The latter site has extensive information on the history and status of pediatric drug issues as well as drug-specific assessment reports.

Bottom Line: Nevertheless, despite aggressive initiatives in the United States, the European Union and elsewhere, the status, knowledge, and safety of drugs for use in children still remains unsatisfactory and largely unknown. In practice, children are often treated as “small adults” because the initiatives still do not get around the fact that most companies, physicians, and parents are loath to perform clinical trials on children. Much of the safety data comes from postmarketing reports of AEs seen in children given drugs aimed primarily at adults. It is not clear how this situation can be resolved. Similarly, the other key safety issues, such as drug–drug, drug–food, and other safety matters are largely unknown in children, and most recommendations in these areas are based on extrapolations from adult data (much of which is also unsatisfactory).

The Elderly

The elderly, like children, also represent a special group in pharmacology for several reasons. There are certain diseases that are seen only or primarily in the elderly (e.g., Alzheimer’s disease or osteoporosis). The elderly tend to have more diseases than the young, especially those that are related to chronic conditions (osteoarthritis, hyperlipidemia) or habits (smoking, alcohol use, obesity). As a consequence, the elderly consume more drugs and for longer durations. Hence, the risk of drug–drug interactions may increase, particularly if there is a decrease in renal or hepatic function. Finally, pharmacokinetics and pharmacodynamics may also be altered in the elderly, producing different effects from those that would occur in younger patients.

Swallowing disorders and dysfunction are often worse in the elderly than in the young. A tablet or other oral preparation that is large, sticky (e.g., having a hydroxy-cellulose outer layer), or oddly shaped may be difficult to swallow and could even get stuck or cause obstruction in the pharynx or esophagus.

Drug–drug, drug–food, drug–alcohol, and drug–disease interactions also may be different in the elderly, but these areas are largely unexplored.

As long ago as 1996, it was clearly noted that 21.3% of community-dwelling elderly patients in the United States received at least 1 of 33 potentially inappropriate medications (Zhan, Sangl, Bierman, Miller, et al., Potentially inappropriate medication use in the community-dwelling elderly. JAMA 2001;286:2823–2829). This led to the creation of a list of medications that should not be used in the elderly (see Fick, Cooper, Wade, Waller, Maclean, Beers, updating the Beers criteria for potentially inappropriate medication use in older adults. Arch Intern Med 2003;163:2716–2724). This is based on the so-called Beers criteria for medication use in the elderly:

• Always to be avoided
  
• Rarely appropriate
  
• Sometimes indicated but often misused

See also an excellent review and update in the Merck Manual (Web Resource 10-14).

The ICH and FDA Guideline

The ICH guideline E7 entitled “Studies in Support of Special Populations: Geriatrics” of 1993 was published by the FDA in August 1994. It is directed primarily at drugs expected to have significant use in diseases of the elderly (e.g., Alzheimer’s disease) or at drugs that are used in large numbers by the elderly (e.g., antihypertensives). The guideline takes an arbitrary definition of geriatric as 65 years or older but recommends seeking out patients 75 years and older for studies. In general, there should be no upper age limit. Nor should the elderly with concomitant diseases specifically be excluded, because these are frequently the patients that most need to be studied.

The guideline recommends that geriatric patients be included in phase III and, at the sponsor’s option, phase II studies in “meaningful numbers.” For diseases “not unique to but present in the elderly,” a minimum of 100 patients studied is recommended. For studies of diseases of the elderly, it is obviously expected that most of the patients studied will be elderly.

Pharmacokinetic studies should be done to determine whether the drug is handled differently in the elderly compared with younger patients. Studies in patients with renal or hepatic insufficiency should be done, although often studies involving the young suffice, and separate studies in the elderly may not be needed. Pharmacodynamic dose-response studies usually do not have to be conducted except for sedative/hypnotic agents and other psychoactive drugs, or where phase II/III studies suggest age-associated issues. Drug–drug interaction studies should be done when appropriate and do not necessarily have to be limited to the elderly.

FDA Guideline and Rule

In 1997, the FDA (62 FR 45313) established the “Geriatric Use” section in drug labeling. In October 2001, the FDA issued a guidance on this rule (Web Resource 10-15). It reviews the requirements for geriatric information in the various sections of approved labeling such as “Indications and Usage” and “Clinical Pharmacology, Warnings, Precautions.” In regard to safety specifically, the FDA states that the labeling should include the following: “A statement describing a specific hazard with use of the drug in the elderly that references appropriate sections (e.g., ‘Contraindications, Warnings, Precautions’) in the labeling for more detailed discussion.”

The FDA also issued a document aimed at consumers entitled “Medicines and You: A Guide for Older Adults,” available at Web Resource 10-16, which summarizes some of the issues in geriatric use of medications.

Reporting requirements for AEs that occur in the elderly are the same as those for other age groups. Data on particular issues for a drug in the elderly should be included in the product labeling.

The elderly present a different picture from that seen with children. There are generally more data available about drugs in the elderly and about conditions more commonly seen in the elderly, such as renal or hepatic insufficiency, diabetes, and alcohol use. It is, in general, easier to study drugs in the elderly than in children, since with children there are often issues of informed consent. Thus, if there are not actual data from studies in the elderly, there are often data on these conditions that allow the healthcare professional to alter doses, change duration of therapy, order special tests, and so on to suit the elderly patient in question with some degree of medical science and data behind the decision. Drug–drug interactions pose a particular risk in the elderly, and much has been written about this (Bressler, Bahl, Mayo Clin Proc 2003;78:1564–1577; see also the editorial and the multiple references in the Archives of Internal Medicine. Polypharmacy: a new paradigm for quality drug therapy in the elderly? Arch Intern Med 2004;164:1957–1959).

The EMA has issued a special report on medicines in the elderly. See Web Resource 10-17. The conclusions include recommendations to define elderly, frailty, and adequate age cutoff points for drugs, to continue adding a specific section on elderly in the Committee for Medicinal Products for Human Use (CHMP) guidelines and to update these where necessary, to emphasize in discussions with companies the need to recruit an adequate number of elderly of various ages in the studies, and to systematically require the appraisal of elderly exposure for drug approval. See also the “Medicines for the Elderly” section at the EMA website (Web Resource 10-18).

Other Special Groups

It is now generally recognized that there is significant biodiversity among humans. There are probably many reasons for this. One major cause relates to drug metabolism pathways. The cytochrome P450 system, which plays a major role in drug metabolism, is well known to exhibit enormous diversity (genetic polymorphism), producing major differences in metabolism of drugs from individual to individual (see Evans, Relling, Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999;286:487–491; Court, A pharmacogenomics primer. J Clin Pharmacol 2007;47:1087–1103; and Nakamura, Pharmacogenomics and drug toxicity [editorial]. N Engl J Med 2008;359:856–858). Because of the differences in how drugs are absorbed, metabolized, distributed, and excreted by groups and by individuals, a more rational and tailored use of drugs will allow the maximization of effectiveness and the minimization of AEs. See the table of cytochrome P450 drug interactions at Web Resource 10-19.

Two further examples of special groups (women and African Americans) follow. In practice, one can create scores of special groups; this may indeed occur if pharmacogenomics fulfills its potential and allows subgroups (and perhaps even individuals) to be identified in terms of who will be at risk for or safe from particular ADRs. How pharmacology and medicine will evolve and characterize these differences in the upcoming years is a fascinating and unanswered question.

Women

Women have, in general, a smaller proportion of body water and a greater proportion of body fat than men. Men and women may metabolize drugs differently. For example, men have more alcohol dehydrogenase than women and thus metabolize the same amount of alcohol more rapidly (Frezza, di Padova, Pozzato, et al., N Engl J Med 1990;322:95–99). Women also handle cardiac drugs differently from men in many instances (Jochmann, Stangl, Garbe, et al., Eur Heart J 2005;26:1585–1595). Pregnant women also handle drugs differently. See Chapter 35.

African Americans

It is well known that different groups in the United States have significant differences in their general health. For example, a review by the Centers for Disease Control and Prevention (MMWR 2005;54[01]:1–3) noted that “for many health conditions, non-Hispanic blacks bear a disproportionate burden of disease, injury, death, and disability.”

Similarly, African Americans may respond less well to certain drugs, such as antihypertensives (Levy, ed., Ethnic and Racial Differences in Response to Medicines: Preserving Individualized Therapy in Managed Pharmaceutical Programs, National Pharmaceutical Council, Reston, VA, 1993) or may have more AEs, such as angioedema associated with angiotensin-converting enzyme inhibitors (Kalow, Trends Pharmacol Sci 1991;12[3]:102–107). From these and other data, additional studies of the effects of drugs in various ethnic or racial groups are desirable. See an excellent commentary on the need for greater diversity in clinical trials by Professor Kenneth Davis of the University of Cincinnati in “African-American Health. Clinical Trial Diversity: The Need and the Challenge,” at Web Resource 10-20.

There are many references on ethnicity and differences in drug metabolism (for example, see Phan, Moore, McLachlan, et al., Ethnic differences in drug metabolism and toxicity from chemotherapy. Expert Opin Drug Metab Toxicol 2009;5[3]:243–257).

The collection and analysis of data based on ethnicity is quite tricky, however. The FDA issued a guidance on the collection of ethnicity data in clinical trials in 2005 (Web Resource 10-21). The guidance offers practical guidelines on how to collect race and ethnicity data in clinical trials and how to present the data in INDs, NDAs, and BLAs. But how ethnicity and the data are to be interpreted in people or groups with mixed ethnic backgrounds is unknown. We await pharmacogenomics.

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