Session V. Regulatory differences and similarities Drug regulation in the United Kingdom The Britisli system under the Medicines Act by which new drug applications are evaluated is described in a step-by-step manner jrom submission of application to the issuance of a clinical trial certificate by the licensing authority, At the end of a period of clinical trials the submission is brought backfor a produet license. Once a drug is marketed it falls within the purview of the adverse reaction monitoring group of the Committee on Safety of Medicines (CSM). Arecent innovation is "monitored release," by which, for a period of time after marketing, case reports are submitted by the pharmaceutical company to the CSM. The advantages of the Britisn system are: (l) the final licensing decisions being made by the academic members of the Committee means that they are insulated from commercial and political pressures, and are addltionaliy reached without undue delay; (2) academic members are not permitted to be retained as consultants to the industry on a long-term basis; (3) evaluation solelyon British. studies is not obligatory-foreign studies are also acceptable. Weaknesses in the system are: (I) reeruitment of people experienced in pharmacology and therapeutics is difficult; (2) there is an inordinate work load on the academic members of the Main Committee and Subcommittees. lmportance of an effective monitoring in the postmarketing stage is emphasized, because the long-term judgment must necessarily be based on wide experience in the filed. The multiplication of the same of similar drugs is deplored, and innovative efforts in the quest for new drugs, especially for rare diseases, are to be encouraged.
Colin T. Dollery, M.B. London, England Department of Clinical Pharmacology, Royal Postgraduate Medical School, Hammersmith Hospital
Prior to the thalidomide catastrophe there was no official system for regulating clinical trials or marketing of new drugs in the United Kingdom. In the interests of speed, a voluntary system was brought into operation through the Committee Reprint requests to: Dr. Colin T. Dollery, Professor of Clinical Pharmacology, Department of Clinical Pharmacology, Royal Postgraduate Medical School, Hammersmith Hospital, London, England.
on Safety of Drugs, better known as the Dunlop Committee. The main features of this arrangement were later incorporated in the Medicines Act, which is now in force. The principal difference of the administrative arrangements under the Medicines Act from the earlier ones under the Dunlop Committee is that they are now backed by the force of law. The best way of describing the British system 689
690
Dollery
SUB COMMITTEE MEMBERS
MAIN COMMITTEE MEMBERS
APPEALS PROCEDURE
Fig. 1. Flow chart of the progress of a submission by a pharmaceutical company to the licensing authority in Great Britain.
is to trace the progress of a submission by a pharmaceutical company to the licensing authority which is part of the Department of Health and Social Security (Fig. 1). After the submissions have been received, they wait in order of arrival until one of the professional staff is available. This waiting time had been as long as 12 months but it is usually 4 to 5 months. In the course of his analysis the Secretariat member will usually seek clarification from the sponsoring company before he prepares his summary and recommendations. This summary goes with the submission to the members of the Subcommittee on Toxicity, Clinical Trials, and Therapeutic Efficacy which considers the submission at its next monthly meeting. The membership of the Subcommittee (September, 1974) is shown in Table I. It spans a wide range of specialist interests and the intention is that each member of the Subcommittee should read those parts of the original submission and summary which lie in his special field with particular care. If the Subcommittee needs further advice, e.g., in ophthalmology, it normally seeks the advice of three outside consultants who do not see the
Clinical Pharmacology and Therapeutics
whole submission but are told the details of the product and its proposed use. The decision in a Subcommittee is taken by the outside members, not by the professional secretariat, although obviously the Secretariat and the Committee usually find themselves in agreement on the main points, although not always on the details. The next stage is for the Subcommittee recommendation to be considered by the Main Committee. Detailed discussion takes pIace at this stage only if the Subcommittee has raised a policy question, or if a member of the Main Committee wishes to challenge the recommendation. However, it is not rare for the Main Committee to modify, refer back, or, in some cases, overrule a Subcommittee decision. If the Main Committee has decided that it does not like the submission this opinion is communicated to the Company, which may ask for a hearing or submit further written evidence before the decision is finally made. If an unfavorable decision is confirmed, there is still a right of appeal to the Medicines Commission, although this has rarely been used. At the end of aperiod of clinical trials, a submission is brought back to apply for a product license and it goes through exactly the same kind of procedures. Once a drug has been marketed it falls into the area of the adverse reaction monitoring group in the Committee on Safety of Medicine (CSM). They may do one of several things. There is an obligation to notify adverse reactions for a new product, and we in England, I think, have been more successful than most other countries, except Sweden, in getting adverse reaction reports from physicians, general practitioners, and hospitals in the entire country. Recently we have been experimenting with what is called monitored release. That means, for every dose or course of treatment administered, or for aperiod of time, areport has to be made to the Committee. For example, when we released prostaglandins for use in abortion we were rather concemed about their safety in clinical practice, and we requested that, for a period, individual case reports must be made by the phacmaceutical company to the Committee. It is expensive, of course, to go through such a
Volume /9 Number 5, Part 2
Drug regulation in United Kingdom
691
Table I. Subcommittee on Toxicity, Clinical Trials, and Therapeutic Efficacy (1974) Prof. D. R. Laurence Sir Austin Bradford Hili Prof. C. T. Dollery Prof. W. Linford Rees Dr. D. F. 1. Mason Prof. F. W. O'Grady Prof. D. V. W. Parke Dr. L. F. Prescott Prof. J. S. Scott Prof. H. K. Weinbren Dr. K. D. Dalton Prof. D. G. Grahame-Smith
monitored release procedure, but I think that it may be a necessary corollary to releasing compounds to the market fairly speedily. The procedures used to regulate new medicines in Britain have been generally admired in some other countries, as weIl as in Britain, and by the pharmaceutical industry. I would like to consider in some detail the strengths and weaknesses of these procedures. Speaking as an individual, and not as a member of the Committee, my remarks are partly critical of the way the Committee conducts its work. But first, as to the advantages of the procedures: The main advantage is that we reach decisions without undue delay and without being influenced by any kind of direct commercial or political pressure. I think that political pressure on governmental agencies in Britain is distinctly less than they are in the United States, so that the problem is truly minor here. We are insulated from it almost completely, because the decisions are made by the academic members; if there were pressure applied-and there have been one or two occasions when there was just a hint of pressure the Committee members would simply resign. All they would lose by resigning would be a sessional fee of $30 for each meeting they attend, but they would gain a great deal of time to do other things. Members of the committee are not forbidden to take part in new drug investigations. It would not be possible to recruit committee members if this were not permitted. However, it is forbidden for anyone to be a retained consultant on
Clinical Pharmacology Medical Statistics Clinical Pharmacology Psychiatry Pharmacology Bacteriology Biochemical Pharmacology Clinical Pharmacology Obstetries & Gynaecology Pathology General Practice Clinical Pharmacology
a long-term basis with a particular pharmaceutical company. We have avoided to a greater extent than any other drug control authority the practice of adopting a chauvinistic or nationalistic position with respect to data originating in other countries. To a certain extent it is understandable that drug control authorities are more likely to have confidence in evidence furnished by people in their own country, whom they know, than from foreigners, whom they do not know. Still, in a scientific sense, this is highly undesirable. My strong belief is that the whole corpus of scientific knowledge about a drug ought to be brought to bear on the licensing decision for a new drug. There have been occasions when the Committee on Safety of Medicines has issued licenses for marketing drugs in the United Kingdom when no studies at all had been done in the United Kingdom. What about the weaknesses in the system? Although the decisions are eventually made by the outside academic members, a great responsibility devolves upon the Professional Secretariat. They process and summarize submissions, because they are the only people who have looked in depth at the whole thing. Generally, the Committee has been fortunate in the quality of people it has been able to recruit for that work, but there is a long-term concern about both recruitment and the career development of people who do this type of work. It is fascinating to do it for a year or two. I have certainly enjoyed the first few years of my work on the CSM, but with time it eventually
692
Dollery
becomes a tedious and repetitive kind of job for the majority of people engaged in it. It is highly desirable that people recruited for this job should be experienced in pharmacology and therapeutics before they join the Medicines Division. For a time the Civil Service Department which controls recruitment to governmental agencies did not recognize this and insisted that more junior medical officers should be hired because they required a lower salary, and could be given "In-service training." I believe that this policy was mistaken. A second problem sterns from the work load of the members of the Subcommittees and the Main Committee. For its effective working, the system relies very heavily upon these individuals for careful reading of the summaries, and the relevant parts of the original submission. Most members of the committees hardly have sufficient time to do this. I normaIly devote about 6 hours of concentrated reading before each meeting of the Subcommittee, and on one occasion when I profoundly disagreed with the summary prepared by one of our medical officers I devoted 5 hours just to reading that one summary to satisfy myself that the points I wanted to make in rebuttal were valid. The work load is probably near bursting point for this relatively small group of peope. This is a cause for concern, and constitutes a potential weakness of the system. What kind of amendments to existing procedures might be useful? In the evolution of a drug study, very different questions arise at different times. The questions relating to a clinical trial certificate almost always concern how weIl the animal pharmacology and toxicity studies have been done. UsuaIly they have been carried out in a proper manner. As to interpretation of these studies, the Professional Secretariat at the CSM is weIl qualified to interpret toxicologic data on animals. I have for some time felt that there was a case for letting them issue the clinical trial certificates, without detailed consideration by the Committee, but with the possibility of chaIlenge afforded at the Committee level. This would avoid needless delay in the issue of clinical trial certificates. When a product comes up for marketing, while safety remains a most important consider-
Clinical Pharmaeology and Therapeutics
ation, efficacy is the dominant issue. The evidence of therapeutic effectiveness is still the part of a drug submission that is most likely to be unsatisfactory. It is astonishing that some major pharmaceutical houses will produce submissions representing years of work, and expenditures of vast sums of money, which are of incredibly low quality. This is a basic problem. Some companies apparently never seem to realize how bad their work is, although the majority are doing work of reasonably good quality. Clearly, the marketing stage is the stage when fuIl committee review is required, perhaps even more thoroughly than is being done at present in the United Kingdom. However, the public and the politicians, as weIl as the health professions, often fail to appreciate that it is not possible to predict very accurately either the safety or relative efficacy at the time a marketing submission is made. The total number of patients treated is too smaIl, and the period of observation too short. Hence, it is essential to have an effective adverse reactions monitoring system. No degree of intensiveness of study in the premarketing stage can adequately substitute for an effective monitoring in the postmarketing phase. In a smaIl country, such as Britain, the number of subjects and the duration of study must be reasonable in relation to the proposed type and chronicity of use of the drug. If we were to insist on several thousand patients being included in each marketing submission, in many cases it simply would not be feasible. We do not take into account relative efficacy at the time we approve marketing, except when there is a question of safety. If an antibacterial compound were submitted for the treatment of urinary infections that is notably less effective than, for instance, ampicillin, we might strike it down on grounds of safety in relation to efficacy. But broadly speaking, if yet another phenothiazine or another tricyclic antidepressant is submitted, we are not aIlowed by law to use relative efficacy or the existence of effective alternative products as a reason for turning it down. After some initial doubt on my part, I think this is probably right. Unless the differences are extreme, the decisions about relative efficacy are probably not easily made by a drug
Volume 19 Number 5. Part 2
control authority. Another thing that must be understood by those who do not serve on a drug control authority is that only a relatively small part of the work is concemed with major innovations in therapy. Many of the substances that come through are probably effective but have no important innovative value. 1 would be prepared to go on record, again as an individual, that if 90% of the drugs approved for marketing by the CSM in the years 1 have served on it had simply been lost forever, the effect upon therapeutics would have been negligible something one has to face in discussing some of the problems of a drug control authority. What is also important to realize and which is not always appreciated by some scientific personnel is that the way drugs are used out in the community after marketing is often very different from the way they have been used during the closely controlled trials which led up to marketing. One member of our Secretariat used to say at the end of his summary: "I think that this drug has been demonstrated to be safe and effective in trials and it must now find its place in the market place." By that he meant that the long-term judgments of the physicians using it would establish how good or bad it was.
Drug regulation in United Kingdom
693
Long-term judgment, in some cases, may be different from the judgment of the people doing very elaborate clinical trials. The doctors out in general practice are not always wrong. One final point: A great many of the submissions that we examine are essentially dealing with trivial reformulations, and a large number of them are intended for use as products for over-the-counter (OTC) sale or for the relief of minor symptoms. The Committee's main preoccupation with them has rightly been with safety, but 1 have always resented that they go out onto the marketplace with the seal of approval of the CSM with little or no evidence of efficacy. It is a welcome change that the Committee now insists on some evidence of efficacy, although the level of evidence sought is less than that required for a major therapeutic substance. One wishes that some means could be found whereby the majority of these trivia need not come before the CSM, but under the Medicines Act they must. Many of these products are more in the nature of consumer products than therapeutic agents. However, if a therapeutic claim is made they have to be considered by the Committee on Safety of Medicines even if at the expenditure of a high proportion of its time.
Colin T. Dollery, M.B. London, England Department of Clinical Pharmacology, Royal Postgraduate Medical School, Hammersmith Hospital
Prior to the thalidomide catastrophe there was no official system for regulating clinical trials or marketing of new drugs in the United Kingdom. In the interests of speed, a voluntary system was brought into operation through the Committee Reprint requests to: Dr. Colin T. Dollery, Professor of Clinical Pharmacology, Department of Clinical Pharmacology, Royal Postgraduate Medical School, Hammersmith Hospital, London, England.
on Safety of Drugs, better known as the Dunlop Committee. The main features of this arrangement were later incorporated in the Medicines Act, which is now in force. The principal difference of the administrative arrangements under the Medicines Act from the earlier ones under the Dunlop Committee is that they are now backed by the force of law. The best way of describing the British system 689
690
Dollery
SUB COMMITTEE MEMBERS
MAIN COMMITTEE MEMBERS
APPEALS PROCEDURE
Fig. 1. Flow chart of the progress of a submission by a pharmaceutical company to the licensing authority in Great Britain.
is to trace the progress of a submission by a pharmaceutical company to the licensing authority which is part of the Department of Health and Social Security (Fig. 1). After the submissions have been received, they wait in order of arrival until one of the professional staff is available. This waiting time had been as long as 12 months but it is usually 4 to 5 months. In the course of his analysis the Secretariat member will usually seek clarification from the sponsoring company before he prepares his summary and recommendations. This summary goes with the submission to the members of the Subcommittee on Toxicity, Clinical Trials, and Therapeutic Efficacy which considers the submission at its next monthly meeting. The membership of the Subcommittee (September, 1974) is shown in Table I. It spans a wide range of specialist interests and the intention is that each member of the Subcommittee should read those parts of the original submission and summary which lie in his special field with particular care. If the Subcommittee needs further advice, e.g., in ophthalmology, it normally seeks the advice of three outside consultants who do not see the
Clinical Pharmacology and Therapeutics
whole submission but are told the details of the product and its proposed use. The decision in a Subcommittee is taken by the outside members, not by the professional secretariat, although obviously the Secretariat and the Committee usually find themselves in agreement on the main points, although not always on the details. The next stage is for the Subcommittee recommendation to be considered by the Main Committee. Detailed discussion takes pIace at this stage only if the Subcommittee has raised a policy question, or if a member of the Main Committee wishes to challenge the recommendation. However, it is not rare for the Main Committee to modify, refer back, or, in some cases, overrule a Subcommittee decision. If the Main Committee has decided that it does not like the submission this opinion is communicated to the Company, which may ask for a hearing or submit further written evidence before the decision is finally made. If an unfavorable decision is confirmed, there is still a right of appeal to the Medicines Commission, although this has rarely been used. At the end of aperiod of clinical trials, a submission is brought back to apply for a product license and it goes through exactly the same kind of procedures. Once a drug has been marketed it falls into the area of the adverse reaction monitoring group in the Committee on Safety of Medicine (CSM). They may do one of several things. There is an obligation to notify adverse reactions for a new product, and we in England, I think, have been more successful than most other countries, except Sweden, in getting adverse reaction reports from physicians, general practitioners, and hospitals in the entire country. Recently we have been experimenting with what is called monitored release. That means, for every dose or course of treatment administered, or for aperiod of time, areport has to be made to the Committee. For example, when we released prostaglandins for use in abortion we were rather concemed about their safety in clinical practice, and we requested that, for a period, individual case reports must be made by the phacmaceutical company to the Committee. It is expensive, of course, to go through such a
Volume /9 Number 5, Part 2
Drug regulation in United Kingdom
691
Table I. Subcommittee on Toxicity, Clinical Trials, and Therapeutic Efficacy (1974) Prof. D. R. Laurence Sir Austin Bradford Hili Prof. C. T. Dollery Prof. W. Linford Rees Dr. D. F. 1. Mason Prof. F. W. O'Grady Prof. D. V. W. Parke Dr. L. F. Prescott Prof. J. S. Scott Prof. H. K. Weinbren Dr. K. D. Dalton Prof. D. G. Grahame-Smith
monitored release procedure, but I think that it may be a necessary corollary to releasing compounds to the market fairly speedily. The procedures used to regulate new medicines in Britain have been generally admired in some other countries, as weIl as in Britain, and by the pharmaceutical industry. I would like to consider in some detail the strengths and weaknesses of these procedures. Speaking as an individual, and not as a member of the Committee, my remarks are partly critical of the way the Committee conducts its work. But first, as to the advantages of the procedures: The main advantage is that we reach decisions without undue delay and without being influenced by any kind of direct commercial or political pressure. I think that political pressure on governmental agencies in Britain is distinctly less than they are in the United States, so that the problem is truly minor here. We are insulated from it almost completely, because the decisions are made by the academic members; if there were pressure applied-and there have been one or two occasions when there was just a hint of pressure the Committee members would simply resign. All they would lose by resigning would be a sessional fee of $30 for each meeting they attend, but they would gain a great deal of time to do other things. Members of the committee are not forbidden to take part in new drug investigations. It would not be possible to recruit committee members if this were not permitted. However, it is forbidden for anyone to be a retained consultant on
Clinical Pharmacology Medical Statistics Clinical Pharmacology Psychiatry Pharmacology Bacteriology Biochemical Pharmacology Clinical Pharmacology Obstetries & Gynaecology Pathology General Practice Clinical Pharmacology
a long-term basis with a particular pharmaceutical company. We have avoided to a greater extent than any other drug control authority the practice of adopting a chauvinistic or nationalistic position with respect to data originating in other countries. To a certain extent it is understandable that drug control authorities are more likely to have confidence in evidence furnished by people in their own country, whom they know, than from foreigners, whom they do not know. Still, in a scientific sense, this is highly undesirable. My strong belief is that the whole corpus of scientific knowledge about a drug ought to be brought to bear on the licensing decision for a new drug. There have been occasions when the Committee on Safety of Medicines has issued licenses for marketing drugs in the United Kingdom when no studies at all had been done in the United Kingdom. What about the weaknesses in the system? Although the decisions are eventually made by the outside academic members, a great responsibility devolves upon the Professional Secretariat. They process and summarize submissions, because they are the only people who have looked in depth at the whole thing. Generally, the Committee has been fortunate in the quality of people it has been able to recruit for that work, but there is a long-term concern about both recruitment and the career development of people who do this type of work. It is fascinating to do it for a year or two. I have certainly enjoyed the first few years of my work on the CSM, but with time it eventually
692
Dollery
becomes a tedious and repetitive kind of job for the majority of people engaged in it. It is highly desirable that people recruited for this job should be experienced in pharmacology and therapeutics before they join the Medicines Division. For a time the Civil Service Department which controls recruitment to governmental agencies did not recognize this and insisted that more junior medical officers should be hired because they required a lower salary, and could be given "In-service training." I believe that this policy was mistaken. A second problem sterns from the work load of the members of the Subcommittees and the Main Committee. For its effective working, the system relies very heavily upon these individuals for careful reading of the summaries, and the relevant parts of the original submission. Most members of the committees hardly have sufficient time to do this. I normaIly devote about 6 hours of concentrated reading before each meeting of the Subcommittee, and on one occasion when I profoundly disagreed with the summary prepared by one of our medical officers I devoted 5 hours just to reading that one summary to satisfy myself that the points I wanted to make in rebuttal were valid. The work load is probably near bursting point for this relatively small group of peope. This is a cause for concern, and constitutes a potential weakness of the system. What kind of amendments to existing procedures might be useful? In the evolution of a drug study, very different questions arise at different times. The questions relating to a clinical trial certificate almost always concern how weIl the animal pharmacology and toxicity studies have been done. UsuaIly they have been carried out in a proper manner. As to interpretation of these studies, the Professional Secretariat at the CSM is weIl qualified to interpret toxicologic data on animals. I have for some time felt that there was a case for letting them issue the clinical trial certificates, without detailed consideration by the Committee, but with the possibility of chaIlenge afforded at the Committee level. This would avoid needless delay in the issue of clinical trial certificates. When a product comes up for marketing, while safety remains a most important consider-
Clinical Pharmaeology and Therapeutics
ation, efficacy is the dominant issue. The evidence of therapeutic effectiveness is still the part of a drug submission that is most likely to be unsatisfactory. It is astonishing that some major pharmaceutical houses will produce submissions representing years of work, and expenditures of vast sums of money, which are of incredibly low quality. This is a basic problem. Some companies apparently never seem to realize how bad their work is, although the majority are doing work of reasonably good quality. Clearly, the marketing stage is the stage when fuIl committee review is required, perhaps even more thoroughly than is being done at present in the United Kingdom. However, the public and the politicians, as weIl as the health professions, often fail to appreciate that it is not possible to predict very accurately either the safety or relative efficacy at the time a marketing submission is made. The total number of patients treated is too smaIl, and the period of observation too short. Hence, it is essential to have an effective adverse reactions monitoring system. No degree of intensiveness of study in the premarketing stage can adequately substitute for an effective monitoring in the postmarketing phase. In a smaIl country, such as Britain, the number of subjects and the duration of study must be reasonable in relation to the proposed type and chronicity of use of the drug. If we were to insist on several thousand patients being included in each marketing submission, in many cases it simply would not be feasible. We do not take into account relative efficacy at the time we approve marketing, except when there is a question of safety. If an antibacterial compound were submitted for the treatment of urinary infections that is notably less effective than, for instance, ampicillin, we might strike it down on grounds of safety in relation to efficacy. But broadly speaking, if yet another phenothiazine or another tricyclic antidepressant is submitted, we are not aIlowed by law to use relative efficacy or the existence of effective alternative products as a reason for turning it down. After some initial doubt on my part, I think this is probably right. Unless the differences are extreme, the decisions about relative efficacy are probably not easily made by a drug
Volume 19 Number 5. Part 2
control authority. Another thing that must be understood by those who do not serve on a drug control authority is that only a relatively small part of the work is concemed with major innovations in therapy. Many of the substances that come through are probably effective but have no important innovative value. 1 would be prepared to go on record, again as an individual, that if 90% of the drugs approved for marketing by the CSM in the years 1 have served on it had simply been lost forever, the effect upon therapeutics would have been negligible something one has to face in discussing some of the problems of a drug control authority. What is also important to realize and which is not always appreciated by some scientific personnel is that the way drugs are used out in the community after marketing is often very different from the way they have been used during the closely controlled trials which led up to marketing. One member of our Secretariat used to say at the end of his summary: "I think that this drug has been demonstrated to be safe and effective in trials and it must now find its place in the market place." By that he meant that the long-term judgments of the physicians using it would establish how good or bad it was.
Drug regulation in United Kingdom
693
Long-term judgment, in some cases, may be different from the judgment of the people doing very elaborate clinical trials. The doctors out in general practice are not always wrong. One final point: A great many of the submissions that we examine are essentially dealing with trivial reformulations, and a large number of them are intended for use as products for over-the-counter (OTC) sale or for the relief of minor symptoms. The Committee's main preoccupation with them has rightly been with safety, but 1 have always resented that they go out onto the marketplace with the seal of approval of the CSM with little or no evidence of efficacy. It is a welcome change that the Committee now insists on some evidence of efficacy, although the level of evidence sought is less than that required for a major therapeutic substance. One wishes that some means could be found whereby the majority of these trivia need not come before the CSM, but under the Medicines Act they must. Many of these products are more in the nature of consumer products than therapeutic agents. However, if a therapeutic claim is made they have to be considered by the Committee on Safety of Medicines even if at the expenditure of a high proportion of its time.
