Drug Safety 5 (Supp!. I): 24-26, 1990 0114-5916/90/000 1-0024/$1.50/0 © ADIS Press Limited
All rights reserved. DSSUP1786
Safety Considerations in Product Development Arthur H. Hayes Jr EM Pharmaceuticals Inc., Hawthorne, New York, New York, USA
Summary
In drug development, about I in 1000 interesting compounds reaches the market. Drug safety is only relative and needs to be considered in the context of efficacy. Ultimately, the standards of safety and efficacy are determined by society. Drug safety can be enhanced by adequate patient education, i.e. patients should understand their disease as well as the risks and benefits of their medication. There is often considerable public pressure on the Government and regulatory authorities to alter some aspects ofthe drug development process. While we should not engage in poor science or alter regulations unthinkingly, the process should be re-examined and re-evaluated as the usual methods of evaluating risk/benefit may not be suitable for a particular disease or patient population. Public pressure has influenced changes in the USA, such as the parallel track testing, early release of drugs etc. H is important to realise that absolute toxicity is rare. Relative toxicity is more usual but may be influenced by many factors such as disease processes, drug dose, duration of administration, kinetic parameters or immunological factors. Clinical considerations in the drug development process include the predictability of adverse reactions in some patient populations, problems of over-dosage, unexpected drug-drug interactions and availability of patient monitoring. Economic factors such as total cost of the drug regimen, availability of alternative therapies, expense of sponsor-initiated special studies and surveillance, liability risk and the potential cost of altered labelling, warning notices and even market withdrawal are also considered. Thus, there are general guidelines, but the clinical, safety and toxicity considerations involved in the development of each drug may be special or unique.
This paper is based on my experience in clinical research, regulatory affairs at the Food and Drug Administration (FDA) and now as head of a pharmaceutical industrial enterprise. Safety considerations in product development is a broad subject and perhaps it may be best to define drug development and safety first. The process of drug development is quite straightforward - it is aimed at bringing chemical substances which prevent or cure disease, ameliorate symptoms or improve the quality of life to the
market as quickly as possible and at a profit. In terms of the number of drugs developed, probably 1 in every 1000 interesting compounds in the laboratory arrives on the pharmacist's shelf. Fundamentally, standards are set by a society and any discussion of safety only makes sense when discussed in the context of a society. Thus, it is society that ultimately determines standards of safety and efficacy. What does safety mean? The Random House dictionary states, 'safety is freedom from the oc-
Safety Considerations in Product Development
currence or risk of injury, danger or loss' or, 'safety is the quality of averting or not causing injury, danger or loss'. According to these general definitions, we do not live in a risk-free world. When we consider drug safety, everyone, if properly informed, would concede that considerations of drug safety only make sense if we know the beneficial effects of the drug in question, i.e. efficacy. In the USA in 1962, amendments were passed which modified the fundamental Food, Drugs and Cosmetics Act of 1938 in such a way that a drug approved after 1962 had to be shown to be effective and safe in its intended use before it could be marketed. The 1962 amendments did not 'invent' efficacy assessments, they merely codified them in law and gave the FDA certain authority to evaluate efficacy in a more formal way. If we say that a drug must be safe and efficacious, the question then arises, for whom is it safe and effective? These concerns are not purely economic but are scientific, clinical and societal concerns. Other important questions include the following: What is the risk? Will it be accepted? Will it be expected by those for whom the drug is intended and by others? A great deal of research is performed and drug labelling is carefully written and often rewritten, but it is usually very hard to predict inappropriate use, availability of other therapies and drug interactions. Physicians, pharmacists and other healthcare professionals have an obligation to educate their patients, who should understand not only the nature of their disease but also the risks and benefits of the medicines they are taking. Efforts are being made in this regard and the population is becoming more aware and knowledgeable. However, individuals must understand that any consideration of drug safety must include efficacy. Sometimes, society, or at least a segment of society, will let the scientific community and the Government know that they are not satisfied with some aspect of the process of drug development. In the USA, many of those with AIDS or AIDS-related complex (ARC) and those who support them, care for them and speak for them have made it clear
25
that the drug development and approval system is not satisfactory for this subpopulation of patients. Their views cannot be dismissed as the opinions of those who do not understand the situation. On the other hand, it does not mean that we should engage in poor science or bend regulations because of public pressure. It means that we should examine and re-evaluate the process. It may be that the usual method of assessing the risk/benefit is not suitable for a particular case, because of either the circumstances of the disease and/or the subpopulation which it affects. There is no question that in the USA some changes, in industry, in scientific and clinical communities and in the way the FDA interprets its mandate and authority to regulate the drugs with respect to safety and efficacy before marketing, have been due to public pressure. Examples are the parallel track testing, 'early' release of drugs and requirements of treatment INDs. An often asked question is 'what kind of toxic attributes of a drug would lead a company to stop its development?' There is no single and certainly no simple answer. However, there are some general guidelines or directions with the accompanying regulations which can be helpful. Firstly, it is important to remember that toxicity studies, however exhaustive, can never demonstrate absolute safety of a drug. They can only more precisely define toxic activity under specific experimental conditions. Thus, the correctness of drug development directly relates to the adequacy of toxicity data and their appropriate interpretation in certain scientific, clinical, economic and indeed societal considerations. Absolute toxicity is rare and obviously development defeating. Relative toxicity is more common and it can be influenced by many things: disease processes, drug dose, duration of administration, kinetic parameters and drug-drug interactions. In addition, toxic effects may be an extension of known pharmacological mechanisms which, in tum, mayor may not underlie the desired action. In either case, predictability of toxicity is high. However, there may be new or even statistically unpredictable toxicity, such as that with an immunological basis, which is often not a consider-
26
ation for premarketing development as the number of subjects/patients studied is too small. It is hard to justify the need for, and the delay in, availability of drugs in order to do a comprehensive 'population allergic reaction screen'. In addition to these scientific aspects, there are clinical considerations which may suggest limiting or ceasing further development of a compound. These include the ease or difficulty of predicting adverse reactions in particular patient populations. This is illustrated by recent experience in the USA with a firm that developed a drug (Roccutane®, Retinoin-A) which scientifically is an excellent cure for refractory, disfiguring acne - a condition that is not just a minor cosmetic annoyance. Unfortunately, this drug that is safe and effective in treating acne can cause gross, serious problems to the fetus. This raises the question of whether it is good policy to allow a drug on the market that is truly beneficial relative to safety considerations in a special subset of the population, while another subset (albeit the 2 populations are in fact subpopulations and have common members) can be severely injured by the drug. A policy of 'the most for the most', i.e. maximum benefit to the maximum number of patients, would not be fair to AIDS patients or to other special populations. Clearly, it
Drug Safety 5 (Suppl. 1) 1990
is not an adequate excuse for withholding the drug from those who derive benefit and where the scientific evidence supports that claim. There are other considerations which have a place in the drug development decision-making process, such as problems of overdosage, unanticipated drug-drug interactions and availability of close patient monitoring. Lastly, economic factors may be important, particularly for the sponsor of the drug. The total cost of the drug regimen, including diagnostic and monitoring procedures, availability of alternative therapies and the expense of sponsor-initiated special studies and monitoring, all influence development decision points. Into this last category, liability risk must be added, together with the potential cost of altered labelling, warning notices and even market withdrawal. Thus, although there are usually logically sequenced guidelines and toxicity matrices arising from a rational approach and prior experience, the decision tree for the development of a specific drug usually has certain individual, even unique characteristics. Author's address: Dr A.H. Hayes Jr, President and CEO, EM Pharmaceuticals Inc., 5 Skyline Drive, Hawthorne, New York, NY 10532, USA.
All rights reserved. DSSUP1786
Safety Considerations in Product Development Arthur H. Hayes Jr EM Pharmaceuticals Inc., Hawthorne, New York, New York, USA
Summary
In drug development, about I in 1000 interesting compounds reaches the market. Drug safety is only relative and needs to be considered in the context of efficacy. Ultimately, the standards of safety and efficacy are determined by society. Drug safety can be enhanced by adequate patient education, i.e. patients should understand their disease as well as the risks and benefits of their medication. There is often considerable public pressure on the Government and regulatory authorities to alter some aspects ofthe drug development process. While we should not engage in poor science or alter regulations unthinkingly, the process should be re-examined and re-evaluated as the usual methods of evaluating risk/benefit may not be suitable for a particular disease or patient population. Public pressure has influenced changes in the USA, such as the parallel track testing, early release of drugs etc. H is important to realise that absolute toxicity is rare. Relative toxicity is more usual but may be influenced by many factors such as disease processes, drug dose, duration of administration, kinetic parameters or immunological factors. Clinical considerations in the drug development process include the predictability of adverse reactions in some patient populations, problems of over-dosage, unexpected drug-drug interactions and availability of patient monitoring. Economic factors such as total cost of the drug regimen, availability of alternative therapies, expense of sponsor-initiated special studies and surveillance, liability risk and the potential cost of altered labelling, warning notices and even market withdrawal are also considered. Thus, there are general guidelines, but the clinical, safety and toxicity considerations involved in the development of each drug may be special or unique.
This paper is based on my experience in clinical research, regulatory affairs at the Food and Drug Administration (FDA) and now as head of a pharmaceutical industrial enterprise. Safety considerations in product development is a broad subject and perhaps it may be best to define drug development and safety first. The process of drug development is quite straightforward - it is aimed at bringing chemical substances which prevent or cure disease, ameliorate symptoms or improve the quality of life to the
market as quickly as possible and at a profit. In terms of the number of drugs developed, probably 1 in every 1000 interesting compounds in the laboratory arrives on the pharmacist's shelf. Fundamentally, standards are set by a society and any discussion of safety only makes sense when discussed in the context of a society. Thus, it is society that ultimately determines standards of safety and efficacy. What does safety mean? The Random House dictionary states, 'safety is freedom from the oc-
Safety Considerations in Product Development
currence or risk of injury, danger or loss' or, 'safety is the quality of averting or not causing injury, danger or loss'. According to these general definitions, we do not live in a risk-free world. When we consider drug safety, everyone, if properly informed, would concede that considerations of drug safety only make sense if we know the beneficial effects of the drug in question, i.e. efficacy. In the USA in 1962, amendments were passed which modified the fundamental Food, Drugs and Cosmetics Act of 1938 in such a way that a drug approved after 1962 had to be shown to be effective and safe in its intended use before it could be marketed. The 1962 amendments did not 'invent' efficacy assessments, they merely codified them in law and gave the FDA certain authority to evaluate efficacy in a more formal way. If we say that a drug must be safe and efficacious, the question then arises, for whom is it safe and effective? These concerns are not purely economic but are scientific, clinical and societal concerns. Other important questions include the following: What is the risk? Will it be accepted? Will it be expected by those for whom the drug is intended and by others? A great deal of research is performed and drug labelling is carefully written and often rewritten, but it is usually very hard to predict inappropriate use, availability of other therapies and drug interactions. Physicians, pharmacists and other healthcare professionals have an obligation to educate their patients, who should understand not only the nature of their disease but also the risks and benefits of the medicines they are taking. Efforts are being made in this regard and the population is becoming more aware and knowledgeable. However, individuals must understand that any consideration of drug safety must include efficacy. Sometimes, society, or at least a segment of society, will let the scientific community and the Government know that they are not satisfied with some aspect of the process of drug development. In the USA, many of those with AIDS or AIDS-related complex (ARC) and those who support them, care for them and speak for them have made it clear
25
that the drug development and approval system is not satisfactory for this subpopulation of patients. Their views cannot be dismissed as the opinions of those who do not understand the situation. On the other hand, it does not mean that we should engage in poor science or bend regulations because of public pressure. It means that we should examine and re-evaluate the process. It may be that the usual method of assessing the risk/benefit is not suitable for a particular case, because of either the circumstances of the disease and/or the subpopulation which it affects. There is no question that in the USA some changes, in industry, in scientific and clinical communities and in the way the FDA interprets its mandate and authority to regulate the drugs with respect to safety and efficacy before marketing, have been due to public pressure. Examples are the parallel track testing, 'early' release of drugs and requirements of treatment INDs. An often asked question is 'what kind of toxic attributes of a drug would lead a company to stop its development?' There is no single and certainly no simple answer. However, there are some general guidelines or directions with the accompanying regulations which can be helpful. Firstly, it is important to remember that toxicity studies, however exhaustive, can never demonstrate absolute safety of a drug. They can only more precisely define toxic activity under specific experimental conditions. Thus, the correctness of drug development directly relates to the adequacy of toxicity data and their appropriate interpretation in certain scientific, clinical, economic and indeed societal considerations. Absolute toxicity is rare and obviously development defeating. Relative toxicity is more common and it can be influenced by many things: disease processes, drug dose, duration of administration, kinetic parameters and drug-drug interactions. In addition, toxic effects may be an extension of known pharmacological mechanisms which, in tum, mayor may not underlie the desired action. In either case, predictability of toxicity is high. However, there may be new or even statistically unpredictable toxicity, such as that with an immunological basis, which is often not a consider-
26
ation for premarketing development as the number of subjects/patients studied is too small. It is hard to justify the need for, and the delay in, availability of drugs in order to do a comprehensive 'population allergic reaction screen'. In addition to these scientific aspects, there are clinical considerations which may suggest limiting or ceasing further development of a compound. These include the ease or difficulty of predicting adverse reactions in particular patient populations. This is illustrated by recent experience in the USA with a firm that developed a drug (Roccutane®, Retinoin-A) which scientifically is an excellent cure for refractory, disfiguring acne - a condition that is not just a minor cosmetic annoyance. Unfortunately, this drug that is safe and effective in treating acne can cause gross, serious problems to the fetus. This raises the question of whether it is good policy to allow a drug on the market that is truly beneficial relative to safety considerations in a special subset of the population, while another subset (albeit the 2 populations are in fact subpopulations and have common members) can be severely injured by the drug. A policy of 'the most for the most', i.e. maximum benefit to the maximum number of patients, would not be fair to AIDS patients or to other special populations. Clearly, it
Drug Safety 5 (Suppl. 1) 1990
is not an adequate excuse for withholding the drug from those who derive benefit and where the scientific evidence supports that claim. There are other considerations which have a place in the drug development decision-making process, such as problems of overdosage, unanticipated drug-drug interactions and availability of close patient monitoring. Lastly, economic factors may be important, particularly for the sponsor of the drug. The total cost of the drug regimen, including diagnostic and monitoring procedures, availability of alternative therapies and the expense of sponsor-initiated special studies and monitoring, all influence development decision points. Into this last category, liability risk must be added, together with the potential cost of altered labelling, warning notices and even market withdrawal. Thus, although there are usually logically sequenced guidelines and toxicity matrices arising from a rational approach and prior experience, the decision tree for the development of a specific drug usually has certain individual, even unique characteristics. Author's address: Dr A.H. Hayes Jr, President and CEO, EM Pharmaceuticals Inc., 5 Skyline Drive, Hawthorne, New York, NY 10532, USA.
