What are the Rules of the Road?

Transcription

1 What are the Rules of the Road? FDA Criteria for Evaluating Drugs and Biologics John H. Powers, MD Associate Clinical Professor of Medicine George Washington University School of Medicine Washington, DC

2 Introduction Defining safety balance of benefits and harms Criteria for evaluating benefits Criteria for evaluating harms What s on the horizon 2

3 Safety of Drugs and Biologics Safety often used to refer to side effects alone or complete absence of all harm Safety is really balance of benefits compared to harms Benefits = people live longer or live better with intervention than without it Harms = adverse consequences with intervention that impair people s ability to live longer or live better Always in context Drug that saves lives with serious side effects (e.g. kidney failure) Drug that increases deaths with symptomatic or lab benefit 3

4 Learning from History If the drug that killed one person in ten thousand was of only minor use therapeutically, it might still be judged to be unsafe, whereas the drug that killed one in a thousand persons, if it had marked and undisputed therapeutic value it would still be a safe and valuable drug J.J. Durett, Chief, Drug Division, FDA, December 1938 Safety and effectiveness dependent upon conditions of use not just if a drug works but in whom, when and on what outcomes 4

5 Learning from History For the most part, sulfapyridine should be used only for patients who are seriously ill. I doubt the advisability of using the drug for patients who have influenza, the common cold, sinusitis or tonsillitis. In such cases, this treatment may be worse than the disease, not only much more uncomfortable, but more dangerous. H. Corwin Hinshaw, Proceedings of Staff Meeting of the Mayo Clinic, 1939;14:771. Studies on prevention failed to show benefit of antimicrobials Robertson O. Newer Knowledge Concerning the inception of pneumonia and it bearing on prevention. Ann Intern Med 1943:18:12. 5

6 Learning from History And now I am starting to use [sulfa] prophylactically. And why not? It has not been proven to work that way! Not scientific you say! Remember we are front line soldiers; when we see the enemy we do not have to wait for orders from headquarters through a long line of red tape. We must go for him, without waiting for the attack!...then why not get the jump on those tough little bacteria? Kill them before they get a foothold. William McIwaine. Virginia Medical Monthly 1941:68:

7 Criteria for Effectiveness Until 1962 FDA could only evaluate safety but not possible since no data on effectiveness Amendments to FD&C Act in 1962 recognized the evidence of effectiveness needed to balance harms Senate hearing in 1962 (based on pricing of drugs) focused on need for substantial evidence of effectiveness Congress held that opinions of practicing clinicians, use in clinical practice, history of market success not appropriate scientific standard 7

8 Criteria for Effectiveness Specific kind of substantial evidence needed to evaluate effectiveness adequate and wellcontrolled investigations Criteria spelled out by FDA based on ineffective antibiotics Panalba case (Upjohn v Finch 1970) 7 different antibiotics shown not to be effective in controlled studies Company claimed that totality of materials based on test tube data, animal studies, use in practice, vigorous sales, clinician opinions met criteria for substantial evidence 8

9 Adequate and Well-Controlled 1. Clear statement of objectives 2. Study design permits valid quantitative comparison with a control 3. Select patients with disease (treatment) or at risk of disease (prevention) 4. Baseline comparability (randomization) 5. Minimize bias (blinding, etc.) 6. Appropriate methods of assessment of outcomes 7. Appropriate methods of analysis 21 CFR

10 Adequate and Well-Controlled These criteria for an adequate and well-controlled clinical investigation set forth in the regulations are minimal requirements for any valid objective study. They provide wide areas for choice for the investigator, and are in no sense unduly rigid and narrow. The regulations appear to be completely reasonable in describing the scientific content of a well-controlled and adequate investigation. In fact, compliance with these standards will not necessarily ensure that the investigation conducted is valid [but] the criteria must be observed to give the study a chance to yield meaningful results. Judge Latchum. US District Court, Pharmaceutical Manufacturers Association v Richardson (1970) 10

11 Regulatory Standard for Safety adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling Food Drug and Cosmetic Act, sec 505 (d) What tests are adequate? Note link to conditions of use safe in one clinical setting might not be safe in another setting 11

12 Overall Considerations Absence of evidence is not evidence of absence Hartung J et al. Anesthesiology 1983;58: Reporting of harms in medical literature generally suboptimal Ioannidis J et al. JAMA Jan 24-31;285(4): Data on safety often obtained outside of randomized clinical trials Randomized trials less susceptible to random error, systematic error (bias and confounding) Need to use other forms of non-randomized data to acquire information on potential harms 12

13 Measurement of Harms Because adverse event reports can take many forms, assessing their materiality is a fact-specific inquiry Something more than the mere existence of adverse event reports is needed to satisfy that standard, but that something more is not limited to statistical significance and can come form the source, content and context of the reports. Justice Sotomayor, Matrixx vs Siracusano, March 22,

14 Quantity of Evidence FD&C Act states adequate and well controlled investigations as plural FDA has generally required two adequate and well-controlled trials per indication in standard approval pathways Supported by legal precedent Final Decision on Benylin 44FR 51512, 518 August 31, 1979 Warner Lambert v Heckler

15 Quantity of Evidence FDA has approved drugs on single study when Excellent design Highly reliable and statistically strong evidence Outcomes related to important clinical benefit like survival Confirmatory study difficult to do on ethical grounds But if results are unclear it is ethical to perform further studies FDAMA Section 115 (1997) - Data from one adequate and well-controlled clinical investigation and confirmatory evidence constitutes substantial evidence 15

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17 Application The Act makes no express exception for drugs used by the terminally ill and no implied exemption is necessary to attain congressional objectives or to avert an unreasonable reading of the terms safe and effective.nothing in the legislative history suggests that Congress intended protection only for persons suffering from curable diseases. Thurgood Marshall, US v Rutherford

18 On the Horizon 21 st Century Cure or 17 th Century Science? Approval of antibiotics suggested based on test tube tests, animal models, dose modeling = totality of evidence Same as evidence rejected with Panalba Recent antibiotics increased deaths despite promising pre-clinical data Approval even if inferior effectiveness for current patients based on presumed future benefits Extension to other therapeutic areas within a year Use of clinical experience same kind of data rejected by Congress in 1962 Increased costs for novel interventions paying for what? 18

19 It s Not that Easy! 19

20 Conclusions Adequate and well-controlled studies relatively new in the history of medicine (post-wwii) Current regulatory standard shown to protect patients used because we were so often wrong before Better drugs and biologics need less evidence to show benefits and acceptable harms Desire to develop cures should not forget lessons learned 20