are rapidly approaching a critical pivotal period; however, in recen t years this technological and scientific leadership in drug development has been threatened by the maze of regula tions and negative forces on innova tion and research. Long delays and the lack of ap- ~-------------~----------~ I The Food and Drug Administration new drugs, "if the drugs are approvproval of new chemical entities have is speeding up the approval process able." had a negative socioeconomic im"It took 32 months on an average pact and have limited the range of for "breakthrough drugs" -those which represent new chemical adfor an NDA (New Drug Applitherapeutic modalities available to vances and those which demoncation) to be approved last year," the physician. This adverse trend if'. strate a high therapeutic gain over Frankel said (Table 1). "That's far turn has an effect on the mounting drugs already on the U.S. market. too long. cost of health care in the United FDA's recognition of the need for "We now have a system with in States, since new drug discoveries drugs to be approved more quickly the agency with industry's support useful in the management of major led to a classification system that to decrease the approval time. We diseases could reduce hospital and rates drugs on the basis of their relhave increased the (pharmaceutical) medical care expenses considerably. ative advance in medicine, chemiscompanies' awareness of the statisThere is an urgent need to reastry, and pharmacology, according to tics, the method of review, of meet- I sess priorities and develop a "big picRobert Frankel, a licensed pharmaing GMPs (good manufacturing ture" awareness of the goals of drug cist who is the deputy associate practicesL and so on. They are legislation and the impact of new director of the Office of New Drug working with us in expediting the rules and regulations on the drug Evaluation in the FDA Bureau of drug approval process without sacdevelopment process. Where will Drugs. The system is being used to rificing the health and safety of the the drugs of the future come from? speed up the drug review process public." If the incentives for investment in which has been heavily critized in research within the private sector Ranking Drug Importance recent years. . are reduced and the innovative Results indicate that "breakThe classification that Frankel thrust of the pharmaceutical industhrough drugs" are receiving aptalks about is one developed in early II try is frustrated, we will have lost provals almost a year faster than the 1974 and now used as an FDA staff I one of our greatest national assets. average "me too" drugs coming on guide ' (BD 4820.3) by the 170 new the market. drug reviewers at FDA. The guide », Editor's note: An excellent referIn a highly animated briefing preence for supplemental reading is the ranks new drugs according to their f sented to American Pharmacy and newly released Pharmaceutical chemical type and their therapeu tic APhA staff members, Frankel drew Manufacturers Association Repotential. on a mountain of statistics that search and Development Section On the chemical scale, a new drug were developed for FDA CommisSeminar Proceedings from 1977 enapplica tion package is assigned a I' sioner Donald Kennedy to undertitled "The Pluralistic Approach to number from one to six to represent score the success of the program. Drug Research," available from its importance. A new molecular en- [' The bottom line, Frankel said, is PMA, 1155 Fifteenth St., NW, tity (NME), an active moiety not yet Wash. DC 20005. that FDA is decreasing the processmarketed in the United States, is ing time for approval of important rated number 1. A new salt, ester, or References

FDA Hastens Approval

of ~Important' New Drugs If

r"t.-

1. W. M . Wardell, " In troduction of New Therapeutic Drugs

in the United States and Grea t Britain: An Interna tio na i Comparison ," Cli,l. Pharmacal. Thn. , 14, p. 773 (1973). 2. D . W. Hansen , "The Pharmaceutical Deve lopment Process: Estima tes of Current Development Costs and Times a nd the Effects of Reg ulator y Changes, " presented at the In s titute of Health Economics and Social Studies, Unive rsi ty of California Seminars, Los Ange les , September

Table 1. FDA Approval Time for New Drug Applications Calendar Year

8-10, 1977.

3. L. H. Sarett, "FDA Regulations a nd Their Influ ence on Future R&D," Re5. Manage. , 1 7 (2), 18 (1974 ). L. Lasag na and W. Wardell, "The Rate of New Drug Discove r y," in R. B. Helms, Ed ., Drug Development and Marketi,lg , American Enterprise In s t itute for Public Policy Research , Washington, DC, 1975, p . 157. 5. " Impact of Disclosure of Safety a nd Efficacy Data on Ex penditures for Pharmaceutical Research and Developme nt ," prepared by F. Dworkin , Economic Analysis Group,. Office of Planni ng and Evaluation , Food a nd Drug Administration , April 1978. 4.

f:

Maximum, months Minimum ' Mean Standard deviation Median Sample size Number approved in 6 months

1974

1975

1976

1977

1978

123.5 5.8 24.5 18.5 19.6

74.1 3.4 22.5 17.3 16.1

59.8 3.4 24 .9 14 .5 21.6

113.9 3.3 26.6 21.7 21.1

120.7 4.6 32.0 27.4 21.0

63 3

87 5

95 2

68 3

101 2

I I ~

~

(

14

American Pharmacy Vol.NS19 , No. 4, Apr.1979/ 182

evaluatio·n by FDA reviewers familiar with the class of drugs. FDA has a cadre · of experts split

deriva t ive of a d rug alrea dy marketed in th is country is ra nked number 2. New form ulations of a drug are ranked number 3 . And so on . On t h e th era peutic scale, a new drug is ra nked" A" if it represe nts an

FDA's Frankel orchestra tes new drug approva ls to speed up important NM Es.

important therapeutic gain, "B" if it appears to be a modest gain, and "e" if it represents little or no therapeutic gain . The "0" and "E" ratings are res er ved for special situations, of which there are few, according to Frankel. The classification of a drug applica t ion- whether for an Investigational New Drug (IND) or New Dr ug Application (NDA)-is initially assigned by a group leader in FDA's Office of New Drug Evaluation. The rating is based on the material submitted by the sponsoring pharmaceutical company and the

into review division s r epresenting six m ajor classifica tio n s of drugs: cardiorenat neuropharmacologicat metabolic and endocrine, anti-infection, oncology and radiopharmaceuticat and surgical and dental. The classification of the therapeutic potential of a particular drug is based on the best subjective opinion of the group leader and staff, Frankel told American Pharmacy. But the classification process doesn't stop there. The status can change during the review process. It can change when new information is submitted by the sponsor. It can change when other submissions are made. It can change on the basis of clinical trials and reports in the literature.

" It's a give and take s itu ation dur ing the r eview process/' Fra nkel said. "However, once the NDA is approved for a particular use, the classifica tion becomes permanent. But the classification soon becomes outda ted beca use other dr ugs are coming down the pipeline. " Understanding the System The classification system has had several uses. It has provided a beleagured FDA with a tool by which to prioritize drugs and to improve the review process for important new chemical and therapeutic advances. It has been an indication to industry as to which drugs will receive priority reviews. It can be a good indicator for physicians and pharmacists watching for signifi-

Drug Approval Scorecard 100

D

New Molecular Entities

23 23

80

60

21 15

15

16 14

20 58 13

40

15 21

11 18

16

10

11 20

0 1963

1964

1965

1966

1967

1968

1969

1970

1971

1972

1973

FDA figures show small but growing number of breakthrough drugs (NMEs) being approved.

American Pharmacy VoI.NS19 , No . 4, Apr.1979/ 183

1974

1975

1976

1977

1978

page 15). "What is also apparent from the statistics, however, is that the vast majority of drugs approved do not offer significant advances over drugs already on the u.s. market/' Frankel said. Of the nearly 1,800 commercial IND applications now pending at FDA, only 47 (fewer than 30/0) are classified as I-A drugs-NMEs offering "important therapeutic gain" (Table 2). Another 205 are 1-8 drugs-NMEs with "modest therapeutic gain." More than 80 0/ 0 of the INDs under review are "e" ca tegory drugs offering "little or no therapeu tic gain." A similar pattern exists with the pending NDAs, Frankel said. Table 3, a summary of NDAs approved since 1973, indicates that fewer than 15 0/0 of all new drugs

called to its attention. The approval time in Table 1 includes both industry drug reviews and FDA's review of submitted material to assure that studies were adequate and well controlled and to establish the benefit I risk ratio, which is an essential part of the philosophy of drug approvat Frankel said. On the other hand, Frankel insists that drugs classified as new molecular entities (NMEs) have received much quicker review since FDA initiated the classification system. In 1978, for example, FDA approved 87 NDAs, of which 21 were NMEs. While it took an average of 32 months to clear those NDAs approved last year, the average time of review of NMEs was 21.0 months, Frank~l points out. And the number of NMEs receiving approval has grown during the 1970s (see graph,

cant new drugs. And it can be used, as Frankel explains on page 17, to get a feeling for what types of new drugs will be marketed in the future. The average FDA drug approval time has been increasing in recent years, as Frankel is quick to admit. Over the past four years, for example, the average number of months for NDA approval climbed from 22.5 in 1975 to 36 in 1978. Although the majority of NDAs were approved in fewer than 20 months, it took more than 10 years for one NDA to reach approval. Frankel points out that a number of factors can delay the review. In the case of the 1978 drug which had taken 10 years, for example, the company had elected not to pursue the approval process for several years after initial deficiencies were

Table 2. Commercial INDs Currently Under FDA Review Therapeutic Potential Type Chemical Type

,

A Important Therapeutic Gain

1 New molecular entity (active

C

D

E

Little or No Therapeutic Gain

Special Situation

DESIIOTC Claim

12 0.67%

2 0.11%

722 40.67%

Total

I

l15 6.47%

566 31.88%

12 0.67%

95 5.35%

-

-

107 6 .02%

3 0.16%

36 2.02%

210 11.83%

-

2 0.11%

251 14.14%

3 0.16%

13 0.73%

55 3.09%

-

-

5 Already marketed drug product (product duplicates a drug marketed in U.S. by another firm)

2 0.11%

14 0.78%

344 19.38%

2 0.11%

3 0.16%

365 20.56%

6 Already marketed drug product

12 0.67%

15 0.84%

219 12.33%

2 0.11%

11 0.61%

259 14.59%

47 2.64%

205 11 .54%

1489 83.88%

16 0.90%

18 1.10%

moiety not yet marketed in U.S.)

2 New salt, ester, or derivative (active moiety is marketed in U.s.) 3 New formulation (compound mar-

keted in U.S. but not dosage form or formulation) 4 New combination (contains two

or more components not previously marketed together)

by the same firm (used for new indications for marketed drugs) Total

16

27 1.52%

B Modest Therapeutic Gain

71 4.00%

1775 100%

American Pharmacy Vol.NS19, No.4, Apr.1979/184

[ [ (

[

\ [

~

Table 3. NDAs Approved from 1973 through 1978 Therapeutic Potential

Chemical Type A

r

r

I r

r

B

C

Total

1

17 4.1 %

43 10.5 %

43 10.5%

103 25.1 %

2

1 0 .2 %

3 0.8%

8 2.0%

12 3.0%

3

11 2.7%

9 2.2%

69 16.8%

89 21.7%

4

1 0.2%

8* 1.9%

9 2.1%

5

3 191 0.7% 46.5%

194 47 .1%

6

1 0 .2 %

Total

30 7.2 %

1 0.2 %

2 0 .5%

4 0 .9%

mitted to reducing the A and B inhouse approval time by 25% in the next three years. Through a series of conferences with the sponsors, we are trying to expedite the approval process-especially on the I-A and I-B NMEs." Although Frankel did not comment specifically on the "drug lag" issue in the United States, he wound up his briefing with some FDA philosophy: "There are no ineffective drugs being approved in the United States today. Furthermore, to say that any drug is completely safe is a misnomer; there is a relative risk/benefit ratio for all drugs. We must know more about stability, toxicity, manufacturing processes, clinical studies, statistics, bioavailability, and bioequivalency than we did before."

-WES 60 321 14.6% 78.2%

411 100%

'Includes one drug in category D.

reaching the marketplace in recent yeai"s were classified as NMEs with important to modest therapeutic ~ gains. Nearly half of all NDAs were granted to 5-C category drugs-the "me too" drugs with "little or no therapeutic gain."

Improving the Quality The new priority system coupled with FDA's increased emphasis on I-A and I-B drugs .has increased in, dustry's awareness of the need to marshal resources on the important new drugs, according to Frankel. INDs and NDAs rated in the A ~ and B categories also rate special FDA handling with the pharmaceutical manufacturers. The sponsors are called to FDA for a conference on these drugs early in the review process. If a sponsor doesn't receive such a call, it can be assumed that the drug application won't receive a priority review. 5-0 the companies are working on insuring that sufficient documentation accompanies applications to achieve the highest possible rating, Frankel said. "The sponsors know FDA is com-

'Snapshot fur the future': 1tends in Drug Development What the FDA statistics on INDs curren tly under review reveal is a good indication about areas of drug development which may lead to better newer medications in future years. Frankel calls it his "snapshot for the future." As the table below shows, one major area of activity appears to be new drugs for metabolic and endoctrine systems. While the total number of commerical INDs currently pending review appears to be low in this area, the number of drugs classified A and B is significantly higher than in any of the other fields. Included in this group of drug products are fertility and antifertility entities and a host of systemic · drugs including androgens, anabolic steroids, hyperglycemics, amino acids, growth hormones, and vasopressins. Although unable to say in what special areas the major activities are, Frankel said, "the entire field offers significant opportunities for new drug products." Another relatively "hot" area of investigation currently is in cardiorenal drugs, with 10 INDs currently receiving priority review in the A category, Frankel points out. It should also be apparent that of the 1,775 INDs now under review, only 47, or fewer than 30/0, fall in the A category. Only 27 are classified as I-A drugs.

I

American Pharmacy VoI.NS19, No . 4, Apr.1979/ 185

b

17

FDA hastens approval of 'important' new drugs.

are rapidly approaching a critical pivotal period; however, in recen t years this technological and scientific leadership in drug development has been...
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